Anti-Inflammatory Medicine - Barry Sears

Anti-Inflammatory Medicine:
Dietary Modulation of Eicosanoids
Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids

Table of Contents
1.0 Defining Anti-inflammatory Medicine .......................................................... 3
2.0 What is Inflammation? .................................................................................. 3

2.1 Types of inflammation .................................................................................

2.2 Mediators of inflammation . ........................................................................
2.3 Clinical markers of inflammation . ..............................................................
2.4 Defining wellness . .......................................................................................
3
3
3
4
3.0 Dietary influences on eicosanoids . ............................................................. 4

3.1 Evolution of the nutrition and the immune response ....................................

3.2 What are eicosanoids? . ................................................................................
3.3 Essential fatty acid metabolism ....................................................................
3.4 Eicosanoid synthesis . ...................................................................................
4
5
5
6
4.0 What is the Zone? .......................................................................................... 6

4.1 What is an anti-inflammatory diet? . ........................................................... 6

4.2 Clinical markers of the Zone ....................................................................... 7
5.0 Other Physiological Effects of Omega-3 Fatty Acids ................................. 7

6.0 Eicosanoids and Heart Disease ................................................................... 7
7.0 Eicosanoids and Neurological Disease ....................................................... 8
8.0 Eicosanoids and Cancer ............................................................................... 8
9.0 Eicosanoids and Inflammatory Conditions ................................................. 8
10.0 Eicosanoids and Obesity .............................................................................. 8
11.0 Eicosanoids and Type 2 Diabetes ................................................................ 9
12.0 Dietary Strategies for the Optimization of Eicosanoids . ........................... 9

12.1 Levels of omega-3 fatty acids required ........................................................ 9

12.2 Fish oil purity ........................................................................................... 9
12.3 Problems with fish oil ................................................................................ 9
12.4 Aspirin ................................................................................................... 10
13.0 Conclusions ................................................................................................. 10

14.0 References ................................................................................................... 11
Inflammation Research Foundation

1.0 Defining Anti-Inflammatory Medicine

For the past 70 years, medicine has done an excellent job
treating acute infectious disease because this type of disease
can often be traced to a single cause, such as bacteria, a virus,
etc. However, the major problem confronting 21st-century
medicine is the treatment of chronic disease. Since chronic
disease is multi-factorial in nature, current medical practice tends
to treat the symptoms, not the underlying cause. Treating only
the symptoms is essentially micro-managing a chronic disease.
Instead, the focus of health care should be on macro-managing
wellness, which can be accomplished by achieving a single, broad
physiological goal:
Decreasing inflammation

The most efficient way of decreasing inflammation is the
modulation of a group of hormones known as eicosanoids.
Decreasing inflammation requires the increased production of
good anti-inflammatory eicosanoids, while simultaneously
decreasing the production of pro-inflammatory bad
eicosanoids. This is because good eicosanoids are powerful
anti-inflammatory agents, whereas bad eicosanoids are
powerful pro-inflammatory agents (1-4). There are many drugs
(aspirin, non-steroidal anti-inflammatory drugs (NSAIDs),
COX-2 inhibitors, and corticosteroids) that can reduce the levels
of bad eicosanoids, but they unfortunately also reduce the
levels of the good eicosanoids. This is why the more powerful
the eicosanoid-suppressing drug (such as a corticosteroid), the
greater the side effects, especially with long-term chronic use.

Often overlooked by modern medicine is that diet is also a
potentially powerful modulator of eicosanoid synthesis since all
eicosanoids must ultimately be derived from the dietary intake
of essential fatty acids (1-4). The most effective long-term way
to induce the body to make more good eicosanoids and fewer
bad eicosanoids is by following an anti-inflammatory diet.
This is the foundation of anti-inflammatory medicine.

Such an anti-inflammatory diet should consist of the
appropriate balance of essential fatty acid precursors required to
produce eicosanoids coupled with consistent insulin control (14).

The modulation of eicosanoids using an anti-inflammatory
diet enables patients to begin to macro-manage their wellness
instead of the chronic use of drugs to micro-manage disease
symptoms. It should be emphasized that an anti-inflammatory
diet is not meant to replace drugs. Its goal is to make drugs
work better at lower concentrations, hence fewer side effects.
However, to do so effectively, patients need to treat the diet
with the same respect that they would for any prescription
drug. This means taking food at the right dose and at the right
time. Finally, there should be clinical markers that can be
monitored by the physician that determine the patients success
in modulating their inflammatory status.
2.0 What is Inflammation?

Understanding inflammation still remains one of the
most complex areas in medicine. Too little of an inflammatory
response, and the body is unable to repel microbial invasions
or heal injuries. Too much of an inflammatory response, and

the immune system begins attacking the bodys own organs
eventually leading to chronic disease.
2.1 Types of inflammation

There are two types of inflammation. The first is classical
inflammation that is associated with pain. This is why a patient
goes to a physician. The pain itself is not the disease, but it is the
damage caused by the chronic disease that generating constant
pain signals. A far more insidious type of inflammation is silent
inflammation. Silent inflammation is below the perception of
pain. As a consequence, the patient does nothing to stop this
type of inflammation. But after years, if not decades, of silent
inflammation there is enough accumulated organ damage that
pain associated with classical inflammation finally manifests.
It should be pointed that silent inflammation is not a disease
any more than free radicals are. However, its presence signifies
an increased inflammatory potential at the cellular level that
indicates the patient is no longer well.
2.2 Mediators of inflammation

Both types of inflammation (classical and silent) are
ultimately mediated by eicosanoids. This hormonal system
is intricately balanced to consist of both pro-inflammatory
eicosanoids that drive the inflammatory process, as well as
equally powerful anti-inflammatory eicosanoids that reverse
the inflammatory process. When operating at peak efficiency,
the checks and balances of these eicosanoids can turn the
inflammatory process on and off with remarkable precision.
But if the levels of pro-inflammatory eicosanoids increase too
much, or the levels of anti-inflammatory eicosanoids are reduced
too much, then the inflammatory response will be indefinitely
turned on at a low level resulting in constant inflammatory
attack at the cellular level that remains below the perception of
pain. This is the definition of silent inflammation.

The mode of action of virtually all anti-inflammatory drugs
is to reduce the elevated levels of pro-inflammatory eicosanoids.
Although there are no drugs that can increase the levels of antiinflammatory eicosanoids, this can be accomplished by an antiinflammatory diet rich in omega-3 fatty acids.
2.3 Clinical markers of inflammation

Although reduction of inflammation has been the key
focus of medicine, there are surprisingly few clinical markers
to quantify its intensity. The most obvious non-invasive
marker is pain. As with pain, the other observations of classical
inflammation (fever, redness, and swelling) are all mediated
by pro-inflammatory eicosanoids. Blood markers of classical
inflammation are also relatively crude. These include increased
white cell counts, exceptionally high levels of C-reactive protein
(CRP), and increased red cell sedimentation rates. Recently
very low levels of CRP have been advanced as a marker of
inflammation (5-8), but because of its rapid increase with acute
infection, the use of this marker as an indicator of chronic lowlevel inflammation remains controversial (9).

Silent inflammation, on the other hand, can be considered
the precursor to classical inflammation and is best measured


by the ratio of two essential fatty acids in the blood. One
is arachidonic acid (AA). the omega-6 essential fatty acid
building block of pro-inflammatory eicosanoids, and the other
is eicosapentaenoic acid (EPA), the omega-3 essential fatty
acid building block of several important anti-inflammatory
eicosanoids. The AA/EPA ratio in the blood is a reliable marker
of the ratio of the same essential fatty acids in every cell in the
body. There is no drug that can reduce the AA/EPA ratio,
however it can be significantly reduced by an anti-inflammatory
diet thus choking off the potential for chronic classical
inflammation to become established.
2.4 Defining Wellness

Its not enough to assume that if patients are not sick,
then they must be well. There are really three distinct stages of
chronic disease as shown below:
Wellness
q
Sub-chronic disease
q
Chronic Disease

Another marker of wellness is fasting insulin, which is a
marker of insulin resistance. It is known that fasting insulin
levels greater than 10 uU/ml have far greater predictive value
for the development of heart disease than elevated levels of LDL
cholesterol (15,16).

The final marker of wellness is the TG/HDL ratio. This is
a marker of metabolic syndrome that precedes type 2 diabetes by
some 8-10 years. The TG/HDL ratio also indicates the relative
size of the LDL particles (17-20). A low ratio is indicative of
primarily large, non-atherogenic LDL particles, whereas a high
TG/HDL ratio indicates a larger population of small, dense
pro-atherogenic LDL particles. Prospective studies indicate that
a low TG/HDL ratio is highly correlated with a reduction in the
development of cardiovascular disease (20)

Elevated levels in these clinical markers are not an
indication that a chronic disease exists yet, however, it does
indicate that the inflammatory potential of the patient has
significantly increased. This means the potential of increased
inflammation at the cellular level has also been significantly
increased. Although the patient not yet ill enough to be
considered to have a chronic disease, the patient can no longer be
considered to be well.

The therapeutic goal of anti-inflammatory medicine is to
move the patient back toward a state of wellness. That can only
be achieved by decreasing the levels of silent inflammation that
can be determined by the clinical markers of wellness.

The opposite of chronic disease is wellness. However as
wellness erodes, the end result will eventually be chronic disease.
The second stage of the disease process is the development
of sub-chronic disease. With sub-chronic disease, both the
physician and patients know they are not well, but they arent
3.0 Dietary influences on eicosanoids
sick enough to be considered truly ill. This stage of sub-chronic

A pro-inflammatory diet will increase silent inflammation,
disease is mediated by increased silent inflammation. The
whereas an anti-inflammatory diet will decrease it. Understanding
final stage is the actual manifestation of some type of chronic
how diet can influence inflammation requires going back in
disease. Only then does the medical establishment throw its
evolutionary time when the immune system, nutrient storage, and
full armament at patients to hopefully drive them back into
diet were intimately coupled together.
sub-chronic illness where the overt
symptoms of chronic disease are
Table 1. Clinical Markers of Wellness
temporarily submerged. However,
it takes many years living in a state
of sub-chronic illness before chronic
Test
Chronic disease Poor: Heading Good: Heading Ideal: State
disease ultimately develops. Thus the
is developing
on a path to
on the path to of wellness
real goal of 21st century medicine
chronic disease wellness
should be to maintain patients in a
AA/EPA ratio
15 or greater
10
3
1.5
state of wellness, and this can only be
accomplished with the reduction of
Fasting Insulin (uU/ml) 15 or greater
13
10
Less than 5
silent inflammation.
Triglyceride/HDL
4 or greater
3
2
Less than 1

The first signs that wellness is
eroding are changes in the markers of
wellness as shown in Table 1.

The best marker of wellness is the AA to EPA ratio in the
3.1 Evolution of nutrition and the immune response
blood. This is the gold standard for determining the extent

Early in the evolution of multi-cellular organisms, a
of silent inflammation in a patient. The ideal AA/EPA ratio
primitive immune system, nutrient storage, and metabolism
is approximately 1.5. This is the AA/EPA ratio found in the
were shared functions in what are known as fat bodies (21).
Japanese (10-13), who are considered the longest-lived and
This primitive immune system that first developed hundreds
healthiest population in the world (14). For reference, the
of millions of years ago is still an intricate part of our present
average AA/EPA ratio of Americans is approximately 12, and for
immune system. It is known as the innate immune system. This
patients with obesity, type 2 diabetes, as well as other chronic
part of the immune response is based on pattern recognition
conditions associated with silent inflammation, the AA/EPA
of microbial invaders. It still represents the first line of defense
ratio is above 20.
against microbial invasion and activates much of the initial


inflammatory response in the body. The primary hormones that
represent key inflammatory mediators of the innate immune
system are eicosanoids.
3.2 What are Eicosanoids?

Eicosanoids are hormones that are derived from longchain essential fatty acids, which were found in the fat bodies
of the earliest multi-cellular organisms. They represent the
first hormones developed by living organisms some 500
million years ago. As the first hormones, they not only allowed
communication between cells, but also provided the primary
inflammatory mediators required to orchestrate an attack against
microbial invaders. Today the interaction of the innate immune
system and eicosanoids still govern the intricate balancing of
inflammatory responses in humans.

In a sense, eicosanoids can be considered super-hormones
capable of modulating the immune system either by turning on
the inflammatory response (bad eicosanoids) or turning off the
inflammatory response (good eicosanoids) depending on which
type of an eicosanoid a cell produces. Unlike typical hormones
that are produced by a particular gland, every cell in your body
is capable of producing eicosanoids. In essence, you have about
100 trillion eicosanoid glands, and the goal of anti-inflammatory
medicine is to maintain an appropriate balance of the good
and bad eicosanoids by controlling the levels of their molecular
building blocks in the membranes of each cell in the body.

The terms good and bad eicosanoids are simply
operational terms, terms that describe very powerful but opposite
physiological actions generated by different eicosanoids. The
patient needs a balance of good and bad eicosanoids to
maintain wellness. This is no different than discussing good
and bad cholesterol. If a patient had no bad cholesterol, he
or she would die. What is required is an appropriate balance
between good and bad cholesterol to help reduce the risk of
heart disease. You can think of eicosanoids the same way, but
realize that theyre vastly more powerful in terms of their impact
on the patients overall wellness as shown below.
Physiological Actions of
Good and Bad Eicosanoids
Good Eicosanoids
Bad Eicosanoids
Prevent blood clots caused by

platelet aggregation
Promote blood clots caused

by platelet aggregation
Cause vasodilation
Cause vasoconstriction
Reduce pain
Promote pain
Decrease cell division
Promote cell division
Enhance the immune system
Depress the immune system

You can see from the list above that bad eicosanoids
appear to have very few redeeming characteristics, since many
chronic diseases can be viewed as an excess of bad eicosanoid
production. Here are some examples of chronic diseases that
result from an excess production of bad eicosanoids.
Heart disease
Stroke
Hypertension
Arthritis
Cancer
Asthma
Depression
Alzheimers

Why not just eliminate all the bad eicosanoids so that
you would never get a heart attack? Its not quite that easy. Lets
take the example of a heart attack. If you didnt have enough
bad eicosanoids, you would probably bleed to death, since
you need some bad eicosanoids to form a clot that stops
bleeding. Of course, if the patient is producing too many bad
eicosanoids their platelets will clot at the wrong time and place.
The same abnormal balance of good and bad eicosanoids is
also the underlying cause of high blood pressure, cancer, immune
disorders, and neurological diseases.

Although most phyisicans are not aware of eicosanoids, the
importance of these hormones was recognized when the 1982
Nobel Prize in Physiology and Medicine was awarded for the
initial discoveries about how they control virtually every function
in the human body, and how aspirin works by altering eicosanoid
levels (22).

Eicosanoids include a broad number of subgroups,
including the following:
Prostaglandins
Thromboxanes
Leukotrienes
Hydroxylated essential fatty acids
Endocannabinoids
Lipoxins
Resolvins

Understanding the relationship of eicosanoids to
inflammation, the development of chronic disease and their
effects on gene expression is one of the prime research areas in
todays biotechnology industry.

3.3 Essential fatty acids and eicosanoids

Essential fatty acids are fats that the body cannot
synthesize, and therefore must be part of the diet. Essential
fatty acids are classified as either omega-6 or omega-3 depending
on the position of the double bonds in the fatty acid molecule.
The positioning of the double bonds determines the threedimensional structure in space and thus the stereochemistry of
the eicosanoids derived from them. Of the eight essential fatty
acids, only three acids can be synthesized into eicosanoids. Two
of these are the omega-6 essential fatty acids, arachidonic acid
(AA) and dihomo gamma linolenic acid (DGLA), and the other
essential fatty acid is eicosapentaenoic acid (EPA), an omega-3
fatty acid.

The eicosanoids derived from AA are generally powerful proinflammatory eicosanoids, whereas those derived from DGLA are
powerful anti-inflammatory eicosanoids. Although those derived


from EPA are virtually neutral in their inflammatory actions, EPA
can play an important role in modulating the balance of DGLA
and AA, and thus the balance of pro- and anti-inflammatory
eicosanoids derived from them.

The key step in this metabolism of eicosanoid precursors
is ultimately controlled by one particular enzyme (delta-5
desaturase), which converts DGLA into AA, the precursor of the
bad eicosanoids.

The activity of this enzyme is profoundly affected by two
dietary components: (a) the levels of insulin and (b) the levels
of EPA. Both can be altered by the diet. Insulin activates the
delta-5 desaturase enzyme to convert DGLA into AA (23,24),
whereas EPA inhibits the same enzyme thus decreasing the levels
of AA and in the process increasing DGLA (1-4, 25,26). The
end result is an increase in DGLA levels and a decrease in AA
levels leading to a better balance of good to bad eicosanoids.
This is shown in Figure 1.
Figure 1.
Dietary Influences on the Metabolism of
Omega-6 Fatty Acids.
Linoleic Acid
Delta 6 Desaturase
Inhibited by Trans Fatty Acids and DHA
Gamma linolenic acid (GLA)
good eicosanoids.

All drugs attempt to reduce the production of proinflammatory eicosanoids by going downstream to hopefully
inhibit a specific enzyme instrumental in synthesizing
eicosanoids. For example, the promise of COX-2 inhibitors was
significantly reduced because these drugs inhibited the formation
of good eicosanoids as well as bad eicosanoids.

A far more promising approach for eicosanoid modulation is
to go upstream to modify the balance of the essential fatty acid
precursors of eicosanoids. This approach modifies the balance of
the essential fatty acid precursors thus enabling the
manipulation of good and bad eicosanoids with elegant
precision. This can only be achieved by an anti-inflammatory diet.
4.0 What Is The Zone?

The concept of maintaining drugs within a therapeutic
zone is well known to physicians. Below that therapeutic zone,
the drug is ineffective, and above that therapeutic zone, the
drug is toxic. The same concept can be applied to the hormones
generated by the food you eat. There are two hormonal systems
that are controlled by the diet. These are eicosanoids and insulin
(1-4). The balance of the dietary intake of essential fatty acids
is a primary factor for eicosanoid synthesis, and the balance
of protein-to-carbohydrate at every meal that controls insulin
secretion. Moreover, there is a great deal of interaction between
these two hormone systems.

Maintaining these two hormone systems within a
therapeutic zone is possible through the consistent application of
an anti-inflammatory diet that is described below.
4.1 What is an anti-inflammatory diet?

Dihomo gamma linolenic acid (DGLA)
Delta 5 Desaturase
Inhibited by Glucagon and EPA

Activated by insulin
Arachidonic Acid (AA)
Good eicosanoids
Bad eicosanoids

There is no drug that can alter the balance of DGLA to AA,
but appropriate dietary intervention with an anti-inflammatory
diet can do so very effectively.
3.4 Drugs that alter eicosanoids

Although many physicians may not be familiar with
eicosanoids, the pharmaceutical industry is, as most of the
standard anti-inflammatory drugs used today alter eicosanoid
levels. These drugs have a common mode of action; they inhibit
enzymes that synthesize pro-inflammatory eicosanoids. However,
they have a very limited potential to alter the balance of good
and bad eicosanoids because they also inhibit the formation of

The simple definition of an anti-inflammatory diet is one
that prevents the excess production of AA thereby reducing the
key substrate for the generation of pro-inflammatory eicosanoids.
To achieve that goal, an anti-inflammatory diet is based upon
consistent insulin control coupled with supplementation with
high-dose fish oil rich in EPA in order to further modulate the
synthesis of AA as described earlier (1-4).

Insulin control is achieved by balancing the protein-tocarbohydrate ratio at each meal (1-4, 27) with the primary source
of dietary fat coming from non-inflammatory monounsaturated
fats. This component of an anti-inflammatory diet can be
described as a moderate-carbohydrate, moderate-protein, and
moderate-fat diet that has approximately one gram of fat for
every two grams of protein and three grams of carbohydrates.
These also represent the newest dietary recommendations from
the Joslin Diabetes Research Center at Harvard Medical School
for the treatment of obesity and type 2 diabetes (28).

The maximum amount of low-fat protein at any meal
should be no bigger than the size and thickness of the palm of
the hand (this is approximately 3 oz. for females and 4 oz. for
males). The majority of carbohydrates should come from low
glycemic-load vegetables and fruits, with high-glycemic starches
and grains (such as bread, potatoes, rice, and pasta) used sparingly
as condiments. This is because the higher the glycemic load of
these carbohydrates, the greater the increase in insulin secretion
and eventually increased silent inflammation. Finally, most of

the fat should consist of non-inflammatory monounsaturated fat
(such as olive oil, slivered almonds, or avocado).

Unlike high-protein diets (that induce ketosis) or
high-carbohydrate diets (that elevate insulin levels), an antiinflammatory diet is based on the balance and moderation of
dietary components at each meal. Such a diet has been shown
to reduce clinical markers of inflammation under controlled
conditions (29, 30).

The other key component of an anti-inflammatory diet
is supplementation with sources rich in the omega-3 fatty acid
EPA. These are found in oily fish or purified fish oils.

Finally, an anti-inflammatory diet should be rich in
polyphenols. These are phytochemicals that give fruits and
vegetables their color. If one is using an anti-inflammatory diet
that is primarily composed of carbohydrates consisting of fruits
and vegetables, then this condition is easily achieved. At high
enough levels, these polyphenols can exert an anti-inflammatory
effect by inhibiting the activation of inducible inflammatory
proteins (such as COX-2 and inflammatory cytokines) that
normally occurs once the innate immune system has been
activated.
4.2 Clinical markers of the Zone

Such a hormonal zone is not some mystical place since
it can be defined by specific blood tests that have already
been described. The ranges of the boundary of the Zone are
summarized below:
AA/EPA ratio
1.5 to 3
Fasting insulin
5 to 10
TG/HDL ratio
1 to 2

These are also the same three clinical tests that define
wellness. Although the AA/EPA ratio is the most sensitive
marker of silent inflammation, the TG/HDL ratio, can be a
very inexpensive initial screen for the potential presence of silent
inflammation in a patient.
5.0 Other Physiological Benefits Of Omega-3
Fatty Acids

Although the effects of omega-3 fatty acids, such as EPA
and docosahexenoic acid (DHA), have their primary benefits
in reducing inflammation by inhibiting the formation of AAderived eicosanoids, they can have several other important
functions that aid in reducing the overall inflammatory load
of a patient. These include the inhibition of toll-like receptors
(such as TLR-4) that are activated by saturated fatty acids
as well as inhibiting the activation of nuclear factor kappaB
that is the transcription element that causes the expression of
various pro-inflammatory proteins, such as the COX-2 enzymes
and inflammatory cytokines (31-33). Omega-3 fatty acids
can also activate other genetic transcription elements (PPAR
alpha and PPAR gamma) that are important in controlling
lipid metabolism and insulin sensitivity (34-36). In addition,
omega-3 fatty acids can inhibit calcium channels thereby
decrease the efflux of calcium into a cell that can also activate
an inflammatory response (37). Finally these same omega-3
fatty acids can alter membrane fluidity enhancing the binding of
hormones to their receptors (38).

With such a wide variety of biological actions, it is not
surprising that clinical studies have indicated significant benefits
can be achieved when the diet is supplemented with adequate
levels of these omega-3 fatty acids.
6.0 Eicosanoids and Heart Disease

Heart disease remains the number-one killer of Americans.
The primary drug used for primary and secondary prevention
of heart disease is still aspirin, even though it has no effect on
cholesterol levels. Aspirin, however, does have a significant
impact on eicosanoids by decreasing the production of those
eicosanoids that promote inflammation, vasoconstriction, and
platelet aggregation (39).

The role of cholesterol as a factor in the development of heart
disease is constantly changing. At first, patients were told that they
only had to worry about their total cholesterol levels. However,
further research found that this wasnt such a strong predictor of
future heart disease. Next came the realization that there is both
good and bad cholesterol. The good cholesterol is found
in the high-density lipoprotein (HDL) particles, and the bad
cholesterol is in the low-density lipoprotein (LDL) particles. This
launched a war against bad cholesterol.

In more recent years, researchers have found that there
are two types of LDL cholesterol particles. One type consists
of large, fluffy LDL particles that appear not to promote
arteriosclerosis or the development of plaques on the arteries.
The other type consists of small dense LDL particles that are
strongly associated with an increased the risk of heart disease. It
appears that the balance of good bad cholesterol (large fluffy
LDL particles) and bad bad cholesterol (small dense LDL)
may be a determining factor in the development of heart disease.
Prospective studies strongly indicate the more bad bad
cholesterol you have, the more likely you are to have a heart
attack while having a high level of the good bad cholesterol isnt
likely to have any adverse health effects (20,40).

How can you tell which type of LDL particle your patient
has? All you have to do is determine the triglycerides to HDL
cholesterol ratio. If the TG/HDL ratio is less than 2, the patient
will have predominantly large fluffy LDL particles that are not
going to cause much harm. If the ratio is greater than 4, the
patient will have primarily small dense LDL particles that can
accelerate the development of atherosclerotic plaquesregardless
of their total cholesterol levels (41, 42). The connection between
the TG/HDL ratio and heart disease was confirmed by studies
from Harvard Medical School (43). This research found that the
higher your TG/HDL ratio the more likely you would have a
heart attack. How much more likely? In that study, those with
the highest TG/HDL ratio had 16 times greater risk compared to
those with the lowest ratio.

The importance of the TG/HDL ratio can be seen from
the recently published results of the on-going Copenhagen Male
Study that studied the effect this ratio has on the long-term
development of heart disease (20). Researchers tracked healthy


patients who had either a low TG/HDL ratio (less than 1.7) or
a high TG/HDL ratio (greater than 6). Patients with the low
TG/HDL ratio who smoked, didnt exercise, had hypertension
and elevated levels of LDL cholesterol, had a much lower risk of
developing heart disease than those who had a far better lifestyle
and metabolic profile, but a higher TG/HDL ratio. This indicates
that lowering the TG/HDL ratio may have a far greater impact
on whether the patient develops heart disease than by improving
lifestyle factors or reducing hypertension and total LDL levels.

The TG/HDL ratio is an indirect marker of both patients
dietary insulin control and fish oil consumption. The definitive
proof of fish oils benefits was demonstrated in the GISSI trial
in which heart disease patients who supplemented their diets
with 0.9 grams of EPA and DHA per day for a four-year period
had a 45-percent reduction in their risk of having a sudden
fatal heart attack, a 20-percent reduction in their risk of total
cardiovascular mortality, and a 10-percent reduction in overall
mortality compared to either a placebo or Vitamin E (44). These
results are equal, if not superior, to the results of statin therapy in
secondary prevention trials.

The recent JELIS study has also confirmed the benefits in
cardiovascular outcome by lowering the AA/EPA ratio (13). In
this study, more than 18,000 Japanese patients were put on statin
therapy for four and a half years. Half of these patients received
1.8 grams per day of EPA, and the other half a placebo consisting
of olive oil. Those receiving the extra EPA had their AA/EPA
ratio reduced by 50%. At the conclusion of the study, those
patients supplemented with EPA had had a 20-percent reduction
in total cardiovascular events compared to those who were on the
placebo. Thus a 20-percent reduction in cardiovascular events
correlated with a 50-percent decrease in the AA/EPA ratio,
whereas those on the placebo had no reduction in their AA/EPA
ratio during the course of the study.

The reason that EPA could have such a profound impact
comes from the fact that statins are the only drugs known
to increase the production of AA (47). Thus statins can
increase silent inflammation. This may be the reason why
the combination of statins and high-dose fish oil rich in EPA
may represent a preferred method of improving outcomes in
cardiovascular patients as demonstrated by the JELIS study (13)
Results of the GISSI Study
7.0 Eicosanoids and Neurological Disease

There is a growing body of research that indicates high
levels of omega-3 fatty acids can have significant benefits in the
treatment of a variety of neurological disorders. It has been
demonstrated that depression (48, 49) can be reduced with
high-dose fish oil supplementation, as well as the disability
caused by multiple sclerosis (50). For example, a decrease of the
AA/EPA ratio from 6 to 1.5 in multiple sclerosis patients was
associated with a 90-percent reduction in acute attacks and a 25percent decrease in overall disability after two years (50). Other
studies have indicated that an elevated AA/EPA ratio is strongly
associated with the severity of depression (51,52). Recent studies
have indicated that children with ADHD have high AA/EPA
ratios, and when those AA/EPA ratios are lowered to the level
found in the Japanese population, then significant behavioral
improvements were observed (53).
Overall mortality
-10%
Cardiovascular mortality -20%
Sudden death
-45%

Another powerful statement on the role of antiinflammatory diet in preventing heart disease mortality comes
from the Lyon Diet Heart Study (45, 46). In this study, heart
attack survivors were split into two groups with one group
put on a diet that followed the American Heart Association
recommendations and the second group put on a diet similar
to the previously described anti-inflammatory diet (rich in
fruits, vegetables, and fish, but containing very low amounts
of omega-6 fatty acids). Although, both groups had the same
cholesterol levels and same triglycerides at the end of four years,
there was, a more than a 70 percent reduction in both fatal
and non-fatal heart attacks in anti-inflammatory diet group
compared to the control diet group. More important, the group
following the anti-inflammatory diet experienced no sudden
deaths (a primary cause of cardiovascular mortality) during the
four years of the study. The only clinical difference between
the two groups that could explain such dramatic cardiovascular
benefits was the reduction in the AA/EPA ratio. The AA/EPA
ratio of the patients in the active group after four years was 6.1
compared to an AA/EPA ratio of 9.0 in the group following
the American Heart Association diet (45). Thus, a 30-percent
reduction in the AA/EPA ratio was associated with a greater than
70-percent reduction in fatal and non-fatal heart attacks despite
the fact that the total cholesterol, total triglycerides, and even the
TG/HDL ratio didnt change for either group. This is why the
AA/EPA ratio is such a powerful predictor of future heart disease
compared to traditional lipid parameters.

8.0 Eicosanoids and Cancer

There is growing realization that cancer has a very strong
inflammatory component. Therefore, it is likely that high-dose
omega-3 fatty acids (EPA and DHA) could have a significant
benefit for cancer patients. Published data indicates that
cachexia can be reduced by high-dose fish oil (54). Furthermore,
it is known that aspirin and non-steroidal anti-inflammatory
drug use is correlated with the decreased incidence of various
cancers (55-57). This may be due to the fact that metastasis are
highly correlated with the over-production of a certain group
bad eicosanoids consisting of hydroxylated essential fatty acids
derived from AA (58).

9.0 Eicosanoids and Inflammatory Conditions

The primary drugs used for treating inflammatory
conditions remain those that reduce the levels of proinflammatory eicosanoids. Clinical studies have indicated that
rheumatoid arthritis (59), Crohns disease (60), inflammatory
bowel disease (61), IgA nephropathy (62), and fibromyalgia

(63) all respond positively to high-dose fish oil. This is probably
due not only to the reduced production of pro-inflammatory
eicosanoids, but also the reduction in the secretion of proinflammatory cytokines, such as tumor necrosis factor (TNF)
and interleukin-1 (64).
10.0 Eicosanoids and Obesity

The association of obesity with type 2 diabetes and
cardiovascular heart disease is a consequence of the ability of the
adipose tissue to be a significant site of inflammation (65-67),
and this inflammation has been shown to be reduced by dietary
omega-3 fatty acids (68) in animal studies.

It has been demonstrated at Harvard Medical School using
iso-caloric diets that the ratio of protein to carbohydrate found
in an anti-inflammatory diet gave superior reductions of elevated
markers of inflammation when compared to an iso-caloric
diet based on the USDA Food Pyramid (29). Likewise it has
been shown that an anti-inflammatory diet generates reduction
in silent inflammation, whereas an iso-caloric Atkins diet
significantly increases silent inflammation (30).

However, the only way to lose excess body fat permanently
is to decrease calorie intake. This means reducing hunger.
Recent research has demonstrated that another eicosanoid
system operating in the brain may be responsible for the
increased appetite that leads to obesity. AA-derived hormones
known as endocannabinoids are powerful stimulators of hunger
(69). It has been shown that an experimental drug that blocks
the binding of endocannabinoids to their receptors results in
weight loss and the reversal of metabolic syndrome (70), but
the neurological side effects of these drugs have stopped their
approval in the United States. However, it has been shown in
animal studies that fish oil can reduce endocannabinoid levels in
the brain (71,72).
11.0 Eicosanoids and Type 2 Diabetes

Currently an estimated 16 million people are afflicted
with type 2 diabetes. This devastating disease puts a patient at
a 2 to 4 times greater risk of dying from heart disease and also
increases the likelihood of kidney failure, blindness, impotence,
amputation, and neuropathy (73).

Obviously a key to treating type 2 diabetes is the reversal
of insulin resistance. Numerous studies indicate that insulin
resistance is strongly associated with increased inflammation
(74-76). It has been shown that when following an antiinflammatory diet, insulin resistance can be reversed in three
days (77). Not surprisingly, the composition of the antiinflammatory diet is virtually identical to newest dietary
recommendations from the Joslin Diabetes Research Center at
Harvard Medical School for treating type 2 diabetes (28).
12.0 Dietary Strategies for Optimization of
Eicosanoids

Not everyone is genetically the same. This is why the
essential fatty acid component of an anti-inflammatory diet can
be further optimized to meet the needs of the individual patient.
12.1 Levels of EPA and DHA required

The first line of optimization is determining the level of
omega-3 supplementation required for the patient. The goal
of anti-inflammatory medicine is reaching an AA/EPA ratio
of approximately 1.5, which is similar to that found in the
Japanese population. The higher the starting AA/EPA ratio in
the patient, the greater the levels of EPA and DHA that will be
required to reach this clinical goal. The most precise clinical
determination of the supplementation required would be analysis
of the AA/EPA ratio of the isolated serum phospholipids. In the
various clinical studies conducted by the Inflammation Research
Foundation, the amount of EPA and DHA required to reduce
the AA/EPA ratio to 1.5 has little to do with the age, weight,
or sex of the patient, but has more to do with the initial levels
of silent inflammation and where that inflammation is located.
Based on numerous blood tests in a wide variety of patients, here
are some suggested guidelines:
Condition
Normal weight, no chronic
disease
Overweight, Type 2 Diabetes,
Cardiovascular Disease
EPA and DHA

Required (Grams/Day)
2.5 g
5
Chronic Pain
7.5
Neurological Conditions
10

These recommended levels of EPA and DHA supplementation are based upon the patient following an anti-inflammatory
diet as described earlier. If the patients diet is rich in highglycemic carbohydrates (that stimulate insulin) or rich in omega6 fatty acids, then the resulting increase in AA due to either of
these two dietary factors may require even higher levels of EPA
and DHA to reduce the AA/EPA ratio to the desired level of 1.5.

12.2 Fish Oil Purity

The amounts EPA and DHA required to reduce the
AA/EPA ratio to 1.5 often requires significant amounts of fish
oil. Thus the potency and purity of the fish oil used should be
of the highest standards. The physician and the patient often
have no way of knowing this information. Fortunately a free
resource exists that solves this problem. The International Fish
Oil Standards (www.ifosprogram.com) is an independent testing
program that uses the most sensitive testing equipment program
available to analyze commercial fish oil products. On its free
Web site, the potencies and purities of fish oil products are listed
from a large number of companies. Because fish oil quantity can
vary greater from lot to lot, it is suggested that a patient make
sure that every lot of fish oil they use is listed on that site, not
just one lot potentially produced several years ago.
12.3 Problems with Fish Oil

The first question the physician often asks is can a patient
take too much fish oil? The answer is potentially yes because if
the AA/EPA ratio is reduced too much, the patient may not be


able to mount an adequate inflammatory response to microbial
invasions. Also a very low AA/EPA ratio may give rise to
inadequate clotting of the blood. This is why blood testing is
useful especially in high dose applications. As long as the AA/
EPA ratio remains above 1.5, then such problems will not occur.
Consuming up to 5 grams per day of EPA and DHA rarely
reduces the AA/EPA ratio to approximately 6. This the level of
the AA/EPA ratio achieved by the subjects in the active group of
the Lyon Diet Heart Study (45).

Although EPA and DHA are powerful nutritional
supplements to reduce the levels of silent inflammation as
measured by the AA/EPA ratio, the same fatty acids also
have the ability to reduce the levels of DGLA. This means a
corresponding reduction in the production of powerful antiinflammatory eicosanoids derived from DGLA. This is because
DHA (and to a lesser extent EPA) are inhibitors of the enzyme
(delta-6 desaturase), which is necessary to produce gamma
linolenic acid (GLA), which is the immediate precursor of
DGLA. As a result, the potential inflammation-modulating
benefits of omega-3 supplementation can never be fully achieved
with fish oils alone.

The seemingly simple solution to this problem (adding
more GLA to fish oil) turns out not to be the solution. This is
because added GLA is rapidly metabolized into DGLA (which
is good), but this increased DGLA becomes a substrate for the
delta-5 desaturase enzyme that converts it into excess AA. This
is known as the spillover effect (1). Although the patient
initially feels a significant improvement with additional GLA
supplementation compared to fish oil alone, often times within a
few months, the benefits will have eroded as the increased DGLA
is being converted into increased AA. In certain cases, all the
anti-inflammatory benefits of fish oil can be totally reversed.

The solution to this problem lies with addition of other
natural inhibitors of the delta-5-desaturase enzyme. The most
specific of these are polyphenols derived from toasted sesame
oil. The toasting of the sesame seeds prior to extraction causes
the breakdown of certain polyphenols to form sesamol, which
is powerful inhibitor of the delta-5 desaturase enzyme (78).
Combining low levels of GLA with the appropriate amount of
toasted sesame oil concentrate in a fish oil product allows the
increasing of DGLA production without the likelihood of the
newly formed DGLA spilling over into increased AA. The
success of this overall strategy can be measured by a decrease in
the AA/DGLA ratio as well as a decrease in silent inflammation
as measured by the decrease in the AA/EPA ratio.

Thus to obtain the full benefits of anti-inflammatory
medicine, the patient needs to decrease silent inflammation
while simultaneously increasing the capacity for increased antiinflammatory eicosanoid production.
12.4 Aspirin

Aspirin remains the most widely used drug in the world
today, yet its ability to impact anti-inflammatory medicine is
now greater than ever. This is due to recent discoveries that
demonstrate very low-dose aspirin (20-40 mg/day) can generate
an entirely new class of powerful anti-inflammatory eicosanoids
known as resolvins (79-81). Resolvins are derived from both
10
EPA and DHA. At higher doses of aspirin, this effect on making

these new anti-inflammatory eicosanoids is entirely abolished
(82). Hence low-dose aspirin and high-dose fish oil can be
combined to even further enhance the ultimate goals of antiinflammatory medicine: A longer and better life.

13.0 Conclusions

The treatment of chronic disease depends upon modulating
inflammation that is ultimately controlled by eicosanoids.
Anti-inflammatory medicine is defined as the use of nutritional
interventions to achieve a better balance of the precursors of
anti-inflammatory to pro-inflammatory eicosanoids. The success
of this strategy can be measured clinically by the decrease of
both the AA/EPA ratio (the marker of silent inflammation) as
well as the AA/DGLA ratio (the marker of anti-inflammation).
Successful application of this dietary intervention gives rise to
the concept of evidence-based wellness with the patient and the
physician working together as a team to move the patient back to
a state of wellness.

In the final analysis, anti-inflammatory medicine is a return
to the foundation of modern medicine when Hippocrates said,
Let food be your medicine, and let medicine be your food.
That statement has never made more sense than when applied to
dietary modulation of eicosanoids.


14.0 References
1. Sears B. The Zone. Regan Books. New York, NY (1995)
2. Sears B. The Anti-Aging Zone. Regan Books. New York, NY
(1999)
3. Sears B. The Omega Rx Zone. Regan Books. New York, NY
(2002)
4. Sears B. The Anti-Inflammation Zone. Regan Books.
New York, NY (2005)
5. Ridker PM. High-sensitivity C-reactive protein.
Circulation 103: 1813-1818 (2001)
6. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, and
Hennekens CH. Inflammation, aspirin, and the risk of
cardiovascular disease in apparently healthy men. N Engl J Med
336: 973-979 (1996)
7. Ridker PM, Glynn RJ, and Hennekens CH. C-reactive
protein adds to the predictive value of total and HDL cholesterol
in determining risk of first myocardial infarction. Circulation
97: 2007-2011 (1997)
8. Pai JK, Pischon T, Ma J, Manson JE, Hankinson SE,
Joshipura K, Curhan GC, Rifai N, Cannuscio CC, Stampfer MJ,
and Rimm EB. Inflammatory markers and the risk of coronary
heart disease in men and women. N Engl J Med 351: 25992610(2004)
13. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y,

Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura
H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, and
Shirato K. Effects of eicosapentaenoic acid on major coronary
events in hypercholesterolaemic patients (JELIS): a randomised
open-label, blinded endpoint analysis. Lancet 369:1090-1098
(2007)
14. Mathers CD, Sadana R, Salomon JA, Murray CJL, and
Lopez AD. Healthy life expectancy in 191 countries, 1999.
Lancet 357: 1685-1691 (2001)
15. Depres J-P, Lamarche B, Mauriege P, Cantin B, Dagenais
GR, Moorjani S, and Lupien P-J. Hyperinsulinemia as an
independent risk factor for ischemic heart disease. N Engl J
Med 334: 952-957 (1996)
16. Lamarche B, Tchernof A, Mauriege P, Cantin B, Dagenais
GR, Lupien PJ, and Despres JP. Fasting insulin and
apolipoprotein levels as a predictor as risk factors for ischemic
heart disease. JAMA 279: 1955-1961 (1998)
17. Reaven GM, Chen YD, Jeppesen J, Maheux P, and Krauss
RM. Insulin resistance and hyperinsulinemia in individuals
with small, dense low density lipoproteins. J Clin Invest 92:
141-146 (1993)
18. Austin MA, Breslow JL, Hennekens CH, Buring JE,
Willett WC, and Krauss RM. Low density lipoprotein subclass
patterns and risk of myocardial infarction. JAMA 260: 19171920 (1988)
9. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir

G, Rumley A, Lowe GD, Pepys MB, and Gudnason V. Creactive protein and other circulating markers of inflammation
in the prediction of coronary heart disease. N Engl J Med 351:
1387-1397 (2004)
19. Tchernof A, Lamarche B, PrudHomme D, Nadeau A,

Moorjani S, Labrie F, Lupien PJ, and Despres JP. The dense
LDL phenotype: associations with plasma lipoprotein levels,
visceral obesity, and hyperinsulinemia. Diabetes Care 19: 629637 (1996)
10. Yamada T, Strong JP, Ishii T, Ueno T, Koyama M, Wagayama

H, Shimizu A, Sakai T, Malcom GT, and Guzman MA. Atherosclerosis and omega-3 fatty acids in the populations of fishing
village and a farming village in Japan. Athero 153: 469-481
(2000)
20. Jeppesen J, Hein HO, Suadicani P, and Gyntelber, F. Low

triglycerides-high high-density lipoprotein cholesterol and the
risk of ischemic heart disease. Arch Intern Med 161: 361-366
(2001)
11. Nakamura T, Takebe K, Tando Y, Arai Y, Yamada N, Ishii M,

Kituchi H, Machida K, Imamura K, and Terada A. Serum fatty
acid composition in normal Japanese and its relationship with
dietary fish and vegetable oil contents and blood lipid levels.
Ann Nutr Metab 39: 261-270 (1995)
12. Kagawa Y, Nishizawa M, Suzuki M, Miyatake T, Hamamoto
T, Goto K, Montaonga E, Izumikawa H, Hirata H, and Eibhara
A. Eicosapolyenoic acids of serum lipids of Japanese islanders
with incidence of cardiovascular diseases. J Nutr Sci Vitaminol
28: 441-453 (1982)
21. Hotamisligil GS. Inflammation and metabolic disorders.

Nature 444: 860-867 (2006)
22. Oates JA. The 1982 Nobel prize in physiology or
medicine. Science 218: 765-768 (1982)
23. Brenner RR. Hormonal modulation of delta-6 and delta-5
desaturases. Prostaglandins Leukot Essent Fatty Acids 68: 151162 (2003)
24. El Boustani S, Gausse JE, Descomps B, Monnier L, Mendy
F, and Crastes de Paulet A. Direct in vivo characterization of
delta-5 desaturase activity in humans by deuterium labeling:
effect of insulin. Metab 38: 315-321 (1989)
11

25. Chapkin RS, Somer SD, and Erickson KL. Dietary
manipulation of macrophage phospholipid classes: selective
increase of dihomo gamma linolenic acid. Lipids 23: 776-770
(1988)
26. Barham JB, Edens MB, Fonteh AN, Johnson MM, Easter L,
and Chilton FH. Addition of eicosapentaenoic acid to gammalinolenic acid-supplemented diets prevents serum arachidonic
acid accumulation in humans. J Nutr 130:1925-1931 (2000)
27. Ludwig DS, Majzoub JA, Al-Zahrani A, Dallal GE, Blanco
I, and Roberts SB. High glycemic index foods, overeating, and
obesity. Pediatrics 103: E26 (1999)
28. www.joslin.org/Files/Nutrition_Guideline_Graded.pdf
29. Pereira MA, Swain J, Goldfine AB, Rifai N, and Ludwig
DS. Effects of a low-glycemic load diet on resting energy
expenditure and heart disease risk factors during weight loss.
JAMA 292: 2482-2890 (2004)
30. Johnston CS, Tjonn SL, Swan PD, White A, Hutchins
H, and Sears B. Ketogenic low-carbohydrate diets have no
metabolic advantage over nonketogenic low-carbohydrate diets.
Am J Clin Nutr 83: 1055-1061 (2006)
31. Lee JY, Plakidas A, Lee WH, Heikkinen A, Chanmugam
P, Bray G, and Hwang DH. Differential modulation of
Toll-like receptors by fatty acids: preferential inhibition by n-3
polyunsaturated fatty acids. J Lipid Res 44:479-486 (2003)
32. Ross JA, Maingay JP, Fearon KC,Sangster K, and Powell JJ.
Eicosapentaenoic acid perturbs signaling via the NF-kappaB
transcriptional pathway in pancreatic tumour cells. Int J Oncol
23: 1733-1738 (2003)
33. Denys A, Hichami A, and Khan NA. n-3 PUFAs modulate
T-cell activation via protein kinase C-alpha and -epsilon and the
NF-kappaB signaling pathway. J Lipid Res 46:752-758 (2005)
34. Li H, Ruan XZ, Powis SH, Fernando R, Mon WY, Wheeler
DC, Moorhead JF, and Varghese Z. EPA and DHA reduce
LPS-induced inflammation responses in HK-2 cells: evidence for
a PPAR-gamma-dependent mechanism. Kidney Int 67: 867874 (2005)
35. Chambrier C, Bastard JP, Rieusset J, Chevillotte E,
Bonnefont-Rousselot D, Therond P, Hainque B, Riou JP, Laville
M, and Vidal H. Eicosapentaenoic acid induces mRNA
expression of peroxisome proliferator-activated receptor gamma.
Obes Res 10: 518-25 (2002)
12
36. Neschen S, Morino K, Dong J, Wang-Fischer Y, Cline GW,

Romanelli AJ, Rossbacher JC, Moore IK, Regittnig W, Munoz
DS, Kim JH, and Shulman GI. N-3 fatty acids preserve insulin
sensitivity in vivo in a peroxisome proliferator-activated receptoralpha-dependent manner. Diabetes 56:1034-1041 (2007)

47. Harris JI, Hibbeln JR, Mackey RH, and Muldoon MF.
Statin treatment alters serum n-3 and n-6 fatty acids in
hypercholesterolemic patients. Prostaglandins Leukot Essent
Fatty Acids 71: 263-269 (2004)
37. Leaf A, Xiao YF, Kang JX, and Billman GE. Membrane
effects of the n-3 fish oil fatty acids, which prevent fatal
ventricular arrhythmias. J Membr Biol 206: 129-139 (2005)
48. Stoll AL, Sverus E, Freeman MP, Rueter S, Zhoyan HA,

Diamond E, Cress KK, and Marangell LB. Omega-3 fatty acids
in bipolar depression: a preliminary double-blind, placebocontrolled trial. Arch Gen Psychiarty 56: 407-412 (1999)
38. Schley PD, Brindley DN, and Field CJ. (n-3) PUFA alter
raft lipid composition and decrease epidermal growth factor
receptor levels in lipid rafts of human breast cancer cells. J Nutr
137: 548-553 (2007)
49. Nemets B, Stahl Z, and Belmaker RH. Addition of omega3 fatty acid to maintenance medication treatment for recurrent
unipolar depressive disorder. Am J Psychiatry 159: 477479(2002)
39. Gaziano JM, Skerrett PJ, and Buring JE. Aspirin in

the treatment and prevention of cardiovascular disease.
Haemostasis 30: 1-13 (2000)
50. Nordvik I, Myhr K-M, Nyland H, and Bjerve KS. Effect of

dietary advice and n-3 supplementation in newly diagnosed MS
patients. Act Neurol Scand 102: 143-149 (2000)
40. Lamarche B, Lemieux I, and Despres JP. The small dense

phenotype and the risk of coronary heart disease epidemiology,
pathophysiology, and therapeutic aspects. Diabetes Metab 25:
199-211 (1999)
51. Maes M. Fatty acid composition in major depression:

decreased n-3 fractions in cholesterol esters and increased
C20:4n6/C20:5n3 ratio in cholesterol ester and phospholipids.
J Affect Dis 38: 35-46 (1996)
41. McNamara JR, Jenner JL, Li Z, Wilson PW, and Schaefer EJ.
Change in LDL particle size is associated with change in plasma
triglyceride concentration. Arterioscler Thromb Vasc Biol 12:
1284-1290 (1992)
52. Adams P, Lawson S, Sanigorski A, and Sinclair AJ.

Arachidonic acid to eicosapentaenoic acid ratio in blood samples
correlates positively with clinical symptoms of depression.
Lipids 31: S157-S161 (1996)
42. Boizel R, Benhamou PY, Lardy B, Laporte F, Foulon T,

and Halmi S. Ratio of triglycerides to HDL cholesterol is an
indicator LDL particle size in patients with type 2 diabetes and
normal HDL cholesterol levels. Diabetes Care 23: 1679-1683
(2000)
53. Sorgi PJ, Hallowell EM, Hutchins HL, and Sears B.

Effects of an open-label pilot study with high-dose EPA/DHA
concentrates on plasma phospholipids and behavior in children
with attention deficit hyperactivity disorder. Nutr J 6:16 (2007)
43. Gaziano JM, Hennekens CH, ODonnell CJ, Breslow JL,

and Buring JE. Fasting triglycerides, high-density lipoproteins
and risk of myocardial infarction. Circulation 96: 2520-2525
(1997)
44. GISSI-Prevenzione Investigators. Dietary supplementation
with n-3 polyunsaturated fatty acids and vitamin E after
myocardial infarction: results of the GISSI-Prevenzione trial.
Lancet 354: 447-455 (1999)
45. deLorgeril M, Salen P, and Delaye J. Effect of a
Mediterranean type of diet on the rate of cardiovascular
complications in patients with coronary artery disease. J Amer
Coll Cardiology 28: 1103-1108 (1996)
46. deLongeril M, Salen P, Martin JL, Monjaud I, Delaye J,
and Mamelle N. Mediterranean diet, traditional risk factors,
and the rate of cardiovascular complications after myocardial
infarction: final report of the Lyon Diet Heart Study.
Circulation 99: 779-785 (1999)
54. Barber MD and Fearon KCH. Tolerance and

incorporation of a high-dose eicosapentaenoic acid diester
emulsion by patients with pancreatic cancer cachexia. Lipids 36
347-351 (2001)
55. Baron JA, and Sandler RS. Nonsteroidal antiinflammatory drugs and cancer prevention. Ann Rev Med 51:
511-523 (2000)
56. Moysich KB, Mettlin C, Piver MS, Natarajan N, Menezes
RJ, and Swede H. Regular use of analgesic drugs and ovarian
cancer risk. Cancer Epidemiol Biomarkers Prev 10: 903-906
(2001)
57. Thun MJ. NSAID use and decreased risk of
gastrointestinal cancers. Gastroenterol Clin North Am 25: 333348. (1996)
59. Kremer JM, Lawrence DA, Petrillo GF, Litts LL, Mullaly
PM, Rynes RI, Stocker RP, Parhami N, Greenstein NS, and
Fuchs BR. Effects of high-dose fish oil on rheumatoid arthritis
after stopping nonsteroidal antiinflammatory drugs. Clinical and
immune correlates. Arthritis Rheum 38: 1107-1114 (1995)
60. Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, and
Miglioli M. Effect of an enteric-coated fish-oil preparation
on relapses in Crohns disease. N Engl J Med 354: 1557-1560
(1996)
61. Belluzzi A, Boschi S, Brignola C, Munarini A, Cariani G,
and Miglio F. Polyunsaturated fatty acids and inflammatory
bowel disease. Am J Clin Nutr 71: 339S-42S (2000)
62. Donadio JV, Grande JP, Bergstralh EJ, Dart RA, Larson TS,
and Spencer DC. The long-term outcome of patients with IgA
nephropathy treated with fish oil in a controlled trial. J Am Soc
Nephrol 10: 1772-1777 (1999)
63. Ozgocmen S, Catal SA, Ardicoglu O, and Kamanli A.
Effect of omega-3 fatty acids in the management of fibromyalgia
syndrome. Int J Clin Pharmacol Ther 38: 362-363 (2000)
64. Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann
G, van der Meer JW, Cannon JG, Rogers TS, Klempner MS,
and Weber PC. The effect of dietary supplementation with n-3
polyunsaturated fatty acids on the synthesis of interleukin-1 and
tumor necrosis factor by mononuclear cells. N Engl J Med 320:
265-271 (1989)
65. Wellen KE and Hotamisligil GS. Obesity-induced
inflammatory changes in adipose tissue. J Clin Invest 112:
1785-1788 (2003)
66. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole
J, Nichols A, Ross JS, Tartaglia LA, and Chen H. Chronic
inflammation in fat plays a crucial role in the development of
obesity-related insulin resistance. J Clin Invest 112: 1821-1830
(2003)
67. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel
RL, and Ferrante AW. Obesity is associated with macrophage
accumulation in adipose tissue. J Clin Invest 112: 1796-1808
(2003)
68. Todoric J, Loffler M, Huber J, Bilban M, Reimers M, Kadl
A, Zeyda M, Waldhausl W, and Stulnig TM. Adipose tissue
inflammation induced by high-fat diet in obese diabetic mice is
prevented by n-3 polyunsaturated fatty acids. Diabetologia 49:
2109-2119 (2006)
58. Tang K and Honn KV. 12(S)-HETE in cancer metastasis.

Adv Exp Med Biol 447: 181-191 (1999)
13

69. Osei-Hyiaman D, Harvey-White J, Batkai S, and Kunos G.
The role of the endocannabinoid system in the control of energy
homeostasis. Int J Obes 2006 30 :S33-38 (2006)
81. Schwab JM, Chiang N, Arita M, and Serhan CN.

Resolvin E1 and protectin D1 activate inflammation-resolution
programmes. Nature 447: 869-874 (2007)
70. Despres JP, Golay A, and Sjostrom L. Effects of

rimonabant on metabolic risk factors in overweight patients with
dyslipidemia. N Engl J Med 353: 2121-2134 (2005)
82. Chiang N, Bermudez EA, Ridker PM, Hurwitz S, and

Serhan CN. Aspirin triggers antiinflammatory 15-epi-lipoxin
A4 and inhibits thromboxane in a randomized human trial.
Proc Natl Acad Sci USA 101: 15178-15183 (2004)
71. Watanabe S, Doshi M, and Hamazaki T. n-3

polyunsaturated fatty acid (PUFA) deficiency elevates and n-3
PUFA enrichment reduces brain 2-arachidonylglycerol level
in mice. Prostaglandins Leukot Essent Fatty Acids 69:51-59
(2003)
72. Oda E. n-3 Fatty acids and the endocannabinoid system.
Am J Clin Nutr 85: 919 (2007)
73. Lotufo PA, Gaziano JM, Chae C, Ajani UA, Moreno-John
G, Buring JE, and Manson JE. Diabetes and all-cause and
coronary heart disease mortality in U.S. male physicans. Arch
Intern Med 161: 242-247 (2001)
74. Shoelson SE, Lee J, and Yuan M. Inflammation and the
IKK beta/I kappa B/NF-kappa B axis in obesity- and dietinduced insulin resistance. Int J Obes Relat Metab Disord 27:
S49-52 (2003)
75. Shoelson SE, Herrero L, and Naaz A. Obesity,
inflammation, and insulin resistance. Gastroenterology 132:
2169-2180 (2007)
76. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, and
Flier JS. TLR4 links innate immunity and fatty acid-induced
insulin resistance. J Clin Invest 116: 3015-3025 (2006)
77. Markovic TP, Furler SM, Jenkins AB, Kragen EW, Campbell
IV, and Chisholm DJ. The determinants of glycemic responses
to diet restriction and weight loss in obesity and NIDDM.
Diabetes Care 21: 687-694 (1998)
78. Chavali SR and Forse RA. Decreased production of
interleukin-6 and prostaglandin E2 associated with inhibition of
delta-5 desaturation of omega-6 fatty acids in mice fed safflower
oil diets supplemented with sesamol. Prostaglandins Leukot
Essent Fatty Acids 61:347-352 (1999)
79. Serhan CN, Arita M, Hong S, and Gotlinger K. Resolvins,
docosatrienes, and neuroprotectins, novel omega-3-derived
mediators, and their endogenous aspirin-triggered epimers.
Lipids 39: 1125-1132 (2004)
80. Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR,
Mirick G, and Moussignac RL. Resolvins: a family of bioactive
products of omega-3 fatty acid transformation circuits initiated
by aspirin treatment that counter proinflammation signals. J
Exp Med 196:1025-1037 (2002)
14

Glossary
Alpha Linolenic Acid (ALA)

This is the short-chain omega-3 fatty acid commonly found
in the diet. Common sources include flaxseed and soy oils.
Unfortunately the metabolism of ALA into the longer-chain
omega-3 fatty acids, such as EPA and DHA, is very inefficient in
humans.
Anti-inflammatory medicine

The use of nutritional interventions to increase antiinflammatory eicosanoids while simultaneously decreasing the
production of pro-inflammatory eicosanoids.
Eicosapentaenoic Acid (EPA)

This is the 20-carbon length long-chain omega-3 fatty acid
that that inhibits the formation of arachidonic acid (AA). Fish
oils are the richest source of EPA.
Essential Fatty Acids

These are fatty acids that the body cant produce and must
be part of the diet. There are two classes of essential fatty acids:
omega-3 and omega-6. These differ by the positions of the
double bonds within the fatty acids. This positioning determines
their three-dimensional structure in space, and hence the type of
eicosanoids that can be made from them.
Gamma Linolenic Acid (GLA)

This is the 20-carbon length long-chain omega-6 fatty acid
that is the immediate precursor of many eicosanoids that increase
inflammation. Egg yolks, fatty red meat, and organ meats are
rich sources of arachidonic acid.

This is the immediate metabolic product of linoleic acid.
This fatty acid is found in certain foods (such as oatmeal), edible
oils (such as borage oil) and also found in human breast milk.
GLA is rapidly metabolized into DGLA and potentially into AA
depending on the activity of the delta-5 desaturase enzyme.
AA/DGLA Ratio
Insulin

This is the marker of the balance of the precursors of proinflammatory to anti-inflammatory eicosanoids. The higher the
AA/DGLA ratio, the less anti-inflammatory eicosanoids will be
produced.
AA/EPA Ratio

The ratio is determined from levels of these long-chain
omega-6 and omega-3 fatty acids in the plasma phospholipids.
The AA/EPA ratio provides a precise measurement of the balance
of eicosanoid precursors in a patient. The higher the AA/EPA
ratio, the greater the levels of silent inflammation.
Dihomo Gamma Linolenic Acid (DGLA)

This is the essential fatty acid precursor of arachidonic
acid. The eicosanoids derived from DGLA have powerful
anti-inflammatory properties, which are opposed to proinflammatory properties of eicosanoids derived from arachidonic
acid (AA). Adequate inhibition of the delta-5 desaturase will
increase the levels of DGLA relative to AA in individual cells.

Insulin in secreted by the beta cells of the pancreas to lower
blood sugar levels. The carbohydrate content of a meal primarily
stimulates insulin secretion. It is essentially a storage hormone
that drives macronutrients (carbohydrates, protein, and fat) into
cells for immediate use or long-term storage. High levels of
insulin activate the delta-5 desaturase enzyme thus increasing AA
levels.
Linoleic Acid

This short-chain omega-6 fatty that can be converted
into arachidonic acid by way of intermediates such as gamma
linolenic acid (GLA) and dihomo gamma linolenic acid
(DGLA). Linoleic acid is the most common dietary form of all
essential fatty acids.
Resolvins

A new class of anti-inflammatory eicosanoids derived from
EPA and DHA that is induced by conformational in the cyclooxygenase (COX) enzyme induced by low dose aspirin
Docosahexaenoic Acid (DHA)

This is the long-chain omega-3 fatty acid that critical for
brain function. DHA is ultimately derived from EPA. DHA is
found in high concentrations in neural tissues.
Eicosanoids

Eicosanoids are hormones derived from 20-carbon essential
fatty acids. These fatty acids are AA, DGLA, and EPA. These
hormones control inflammation. It is balance of eicosanoids that
comes from long-chain omega-3 and omega-6 essential fatty
acids that ultimately determines a persons state of wellness. The
1982 Nobel Prize in Medicine was awarded for understanding
the role of eicosanoids in human disease.
15
The Inflammation Research Foundation is a non-profit 501(c) corporation whose mission includes
physician education on the potential of anti-inflammatory medicine and sponsoring of clinical trials using
anti-inflammatory medicine in the treatment of a variety of chronic disease conditions.

21 Tioga Way, Marblehead, MA 01945
Tel: 781-639-1214 Fax: 781-639-8154
www.inflammationresearchfoundation.org
16
Anti-Inflammatory Medicine:
Anti-Inflammatory Diets
Anti-Inflammatory Medicine: Anti-Inflammatory Diets

Introduction
greater the level of silent inflammation in various organs

(2-4).
Although the development of obesity and type 2 diabetes

have become worldwide epidemics, current medical
interventions appear powerless to stop them (1). Even
more discouraging is the fact that there is no consensus
that defines the molecular causes of these conditions.
Traditional thinking maintains that obesity and type 2
diabetes stem from a lack of willpower, and that if the
individual would only eat less and exercise more, these
epidemics would soon diminish. This review presents
an alternative position suggesting that in those with a
genetic predisposition, obesity and type 2 diabetes arise
from low-level chronic inflammation induced by diet.
This alternative viewpoint presents obesity and diabetes as
metabolic disorders caused by inflammation and spread by
mechanisms that have many similarities to cancer.
Since silent inflammation can now be measured, it is

found to be strongly associated with virtually every chronic
disease condition, but for the purpose of this review, I will
discuss its implications in the development of obesity and
diabetes.
Types of Inflammation
There are two distinct types of inflammation. The first is
an acute and intense pro-inflammatory response causing
significant pain. This is considered classical inflammation.
More recently recognized is chronic low-level inflammation
that is below the threshold of pain. This is what I term
silent inflammation (2-4). Since there is no pain
associated with this type of inflammation, nothing is done
to stop it and thus it can linger for years, if not decades,
while causing continuing organ damage. If there is enough
organ damage, then chronic disease finally appears. This
not only includes obesity and type 2 diabetes, but also
many other chronic disease conditions (2-4).
Markers of Silent Inflammation

It is very difficult to discuss this new concept of silent
inflammation if you cant measure it, especially since there
is no pain associated with it. It is only recently that new
clinical markers of silent inflammation have emerged. The
first of these clinical markers is high-sensitivity C-reactive
protein (hs-CRP). It is not a very selective marker since
simple infections can raise it dramatically, and it is a not a
very specific marker of the inflammatory process (5-7). A
much more selective marker of silent inflammation is the
ratio of two key fatty acids in the blood. The first is the
omega-6 fatty acid, arachidonic acid (AA), which is the
precursor to pro-inflammatory eicosanoids. The other fatty
acid is the omega-3 fatty acid, eicosapentaenoic acid (EPA),
which generates anti-inflammatory eicosanoids. The
higher the AA/EPA ratio in the blood of an individual, the
1
Diet-induced Silent Inflammation

There has not been one particular dietary change in
the past 25 years that has increased the levels of silent
inflammation. However, there has been a convergence
of three distinct dietary changes that I term, The Perfect
Nutritional Storm (4). These dietary factors include:
Increased consumption of refined, high glycemic-load
carbohydrates
Increased consumption of refined vegetable oils rich
in omega-6 fatty acids
Decreased consumption of long-chain omega-3 fatty
acids
The first of these dietary changes is the increased
consumption of refined high glycemic-load carbohydrates.
The glycemic load of a particular carbohydrate is defined
as the amount that is consumed at a meal multiplied by its
rate of entry as glucose into the bloodstream (i.e. glycemic
index). These high glycemic-load carbohydrates are not
only the major components in virtually all processed foods,
but also in bread products and pasta. As the cost of refined
carbohydrate production has decreased in the past 25 years,
the availability of products made from these ingredients
has dramatically increased (8). Increased consumption of
finished food products with a high glycemic load results in
the increased secretion of the insulin necessary to lower the
resulting post-prandial rise in blood glucose (9,10).
Increased insulin production alone is not sufficient to
explain the rapid increase in silent inflammation. This
requires the presence of another recent dietary component:
The increased consumption of refined vegetable oils rich
in omega-6 fatty acids. The coupling of an increase in
insulin production with an increase in omega-6 fatty acid
consumption results in the increase of AA, especially in
those who are genetically predisposed (11). Since refined
high-glycemic carbohydrates and refined vegetables
are now the cheapest source of calories (12-14), it not
surprising that the combination of these two dietary
trends has increased the production of AA thus leading

to an epidemic increase in silent inflammation. This can
be understood by illustrating the metabolic pathway of
linoleic acid conversion to AA as shown below in Figure 1.
Figure 1.
Metabolism of Omega-6 Fatty Acids
to make pro-inflammatory eicosanoids. In this regard,

increased consumption of EPA dilutes out existing AA,
thus decreasing the production of pro-inflammatory
eicosanoids. Finally, EPA is the molecular building block
for powerful anti-inflammatory eicosanoids known as
resolvins (19-22).
Unfortunately, the consumption of long-chain omega-3
fatty acids, such as EPA, has dramatically decreased over
the past century (23). With the decrease in EPA intake
coupled with the increase of refined carbohydrates and
vegetable oils, the dietary stage has been set for a dramatic
increase in silent inflammation.
Linoleic acid
Delta 6 Desaturase
Activated by Insulin
Gamma linolenic acid (GLA)

Dihomo gamma linolenic acid (DGLA)
Delta 5 Desaturase
Activated by Insulin
Inhibited by EPA
The two rate-limiting steps in this metabolic cascade of

linoleic acid to arachidonic acid are the enzymes delta-6
and delta-5 desaturase. These enzymes insert cis double
bonds into unique positions in the omega-6 fatty acid
molecule. Normally, these conversion steps are very slow,
thus limiting the production of AA. However, insulin is
a strong activator of each of these enzymes (15-18). This
means that a high glycemic-load diet coupled with the
increased intake of vegetable oils rich in linoleic acid will
lead to increased production of AA and a corresponding
increase in silent inflammation.
Finally, there is the role of the omega-3 fatty acid
EPA in this metabolic cascade and its effect on silent
inflammation. In high enough concentrations, EPA can
inhibit the activity of the delta-6 desaturase enzyme thus
reducing AA formation by acting as a feedback inhibitor.
Furthermore, increased EPA content in the membrane
phospholipids decreases the release of AA that is necessary
Obesity Induced by Silent

Inflammation
The body has a unique way of initially dealing with
elevated AA levels that would otherwise increase silent
inflammation. This is through the generation of healthy
new fat cells. Derivatives of AA can stimulate the stem
cells in the adipose tissue to create new fat cells (24, 25) for
the purpose of storing any excess AA, and thus preventing
it from circulating in the blood. In fact, the definition
of a healthy fat cell is one that can increase the storage of
triglycerides. By doing this, the adipose tissue if composed
of healthy fat cells, becomes analogous to a toxic waste
dump that sequesters any increased production of AA.
This is clearly illustrated in children in which the greater
the BMI, the higher the levels of AA in the adipose tissue
(26).
There is also the problem of inherent insulin resistance that
is often observed in genetically predisposed individuals.
Early studies by Reaven demonstrated that insulin response
to a defined intake of carbohydrates in healthy, normal
weight individuals could be broken into four distinct
quartiles (27). This would suggest that the lowest quartile
of normal, healthy individuals could tolerate higher levels
of carbohydrate consumption without a significant increase
in their insulin secretion. However, it also suggests that
perhaps 75% (the three highest insulin-secreting quartiles)
of the U.S. adult population would have a more difficult
time with increased carbohydrate consumption, with those
in the highest quartile being the first to feel the effects of
increased carbohydrate consumption. Since more than
66% of the U.S. adult population is currently overweight
or obese (28), this may indicate the most insulin-sensitive
three quartiles of the general population may already be
affected by the Perfect Nutritional Storm.
2

The Fat Trap
Genetically predisposed individuals have a fat trap that
can be activated by increased insulin levels (4). Incoming
calories that are not immediately used are converted into
fat by the liver for long-term storage in the adipose tissue.
If a genetically predisposed individual has a high insulin
response to carbohydrates, then the increased insulin will
accelerate that storage by driving glucose into the fat cells
for conversion into glycerol. Simultaneously, elevated
insulin will also increase the levels of fatty acid binding
proteins in the fat cell that facilitate the transfer of free
fatty acids into the fat cell (29-32). The combination
of the two factors will increase the deposit rates of
triglycerides in the adipose tissue. However, the same
elevated insulin will inhibit the hormone-sensitive lipase
required to release the stored fat for conversion into ATP
by the peripheral tissues (33-35). Circulating fat can be
considered high-octane fuel compared to carbohydrates for
ATP synthesis since far more ATP can be produced from a
gram of fat compared to a gram of carbohydrate.
In essence, the individual with an active fat trap is
constantly starved for ATP production. Since a typical cell
can only store about 10 seconds worth of ATP, the lack of
a constant supply of stored fat released from the adipose
tissue to continually replace ATP forces the individual to
either eat more (to get more fat into the bloodstream to
make ATP) or exercise less (to conserve their existing ATP
levels). In other words, they become a glutton or a sloth.
These observations associated with obesity are not the cause
of obesity, but the results of the metabolic consequences of
elevated insulin levels on fat cell metabolism (4, 36).
This also explains the poor success of genetically
predisposed individuals adherance to the long-term protocol
of simply eating less and exercising more. If they eat less,
there will be less available raw material to make ATP. If
their fat trap is still operating, then the only alternative
for the body is to begin to cannibalize its own muscle and
organs to supply the necessary raw materials for continued
ATP production. They will initially lose weight, but not
nearly the amount of body fat that would be predicted.
The same is true for exercising more. If the fat trap is still
active, increased exercise will consume existing ATP stores
at a faster rate, again forcing the body to cannibalize muscle
mass and organs for the raw materials necessary to maintain
ATP levels. This is exactly what happens in genetically
bred obese mice that are forced to eat less and exercise more
(37). With increased exercise and calorie restriction there is
weight loss. However, upon autopsy their fat stores are still
robust, but there is significant wasting of muscle mass and
3
organs. There is no reason to believe the same phenomenon

is not happening to human subjects. In addition, with
calorie restriction comes an increase in the hunger hormone
ghrelin (38,39). So in addition to cannibalizing tissue, the
genetically predisposed individual with an active fat trap
has even greater hunger when eating less. Under these
conditions, willpower alone will be insufficient to continue
such adverse metabolic consequences for an extended
period of time.
The Life and Death of a Fat Cell

The definition of a healthy fat cell is one that can easily
expand to sequester incoming fats and in particular
AA, and depending on the genetic predisposition of an
individual, also governs the release of stored fat for ATP
production.
The problem begins when AA levels become too great in a
particular fat cell. The fat cell response to insulin signaling
becomes compromised due to internal inflammation. This
interrupts the flow of glucose into the fat cell to provide
the necessary glycerol for fatty acid storage. As a result,
the fat cell has a more difficult time sequestering newly
formed AA as well as other fatty acids. At the same time,
insulin inhibition of the hormone sensitive lipase becomes
compromised because of the same disruption in insulin
signaling. These are the hallmarks of insulin resistance
in the fat cell that arise far earlier than insulin resistance
in muscle cells (40,41). As a result, not only do greater
amounts of AA remain in circulation to be taken up by
other cells potentially leading to insulin resistance in the
muscle cells (causing increased hyperinsulinemia), but
also the compromised fat cell is releasing greater amounts
of previously sequestered AA from fat cells into the
circulation (42).
As the levels of AA further increase beyond a critical
threshold barrier in any one particular fat cell, cell death
can take place. The necrosis of that particular fat cell
causes a migration of macrophages into the adipose tissue
(43-45). This increase in macrophage accumulation
in the adipose tissue is clearly seen in both animal
models of obesity as well as in humans. These newly
recruited macrophages cause the secretion of additional
inflammatory mediators, such as IL-6 and TNF, which
increase inflammation within the adipose tissue (4658). The amount of macrophage accumulation can be
significantly reduced upon supplementation with highdose fish oil rich in EPA to reduce inflammation in the
adipose tissue (59, 60).

With inflamed adipose tissue, IL-6 derived from the
macrophages can exit into the circulatory system to cause
an increase in CRP formation in the liver. Likewise TNF
generated by the same macrophages cause further insulin
resistance in the surrounding fat cells, thus decreasing their
ability to sequester newly formed AA as well as causing the
release of more stored AA into the circulatory system. In
many ways, the staging area for insulin resistance in other
organs (muscles, liver, and eventually the pancreas) can be
considered to start in the adipose tissue.
Lipotoxicity:
Understanding Obesity as a Cancer
As long as the adipose tissue is composed of healthy fat
cells, any increased production of dietary-induced AA can
be safely handled by their continued expansion. It is only
when normal fat cell metabolism becomes compromised by
increased AA accumulation that lipotoxicity can occur (59,
60).
This is why obesity and cancer share many similarities.
They are both characterized by increased inflammation
(as marked by increased macrophage concentration),
seemingly uncontrolled growth, as well as metastasis
to distant sites. The excess fat mass in an individual
who is actively sequestering AA from the circulation
represents a benign tumor because it does not compromise
physiological function. This explains why approximately
one-third of obese individuals are actually quite healthy
(63). These individuals are known as the metabolically
healthy obese (64) and appear to have higher levels of the
adipose-derived hormone adiponectin (65).
However, the accelerated release of stored AA from the
fat mass into the circulation is similar to the metastatic
spread of a tumor, only now it is silent inflammation
that is spreading. This metastasis of silent inflammation
is characterized by lipotoxicity, which is the enhanced
deposition of lipid droplets in organs (muscle, liver, and
pancreas) that are not designed for lipid storage. If this
accumulation of lipid droplets is also enriched in AA, then
the development of type 2 diabetes will be accelerated.
One of the first indications that lipotoxicity is taking
place is the appearance of metabolic syndrome. Metabolic
syndrome can be considered to be pre-diabetes. It is
characterized by a combination of clinical markers, such
as a high TG/HDL ratio, increasing abdominal fat, and
hyperinsulinemia. Recent data indicate that there is a
strong correlation between metabolic syndrome and levels
of AA in the adipose tissue (40).
Left untreated, metabolic syndrome will usually result

in the development of type 2 diabetes within 8-10 years.
During this time period, the insulin resistance of the
individual is continually increasing. This will cause even
more AA formation if consumption of omega-6 fatty acids
remains high. Since the fat cells are now compromised in
their ability to sequester this increased AA production, it
remains in the blood to be picked up by other organs.
The final development of type 2 diabetes only occurs when
the lipotoxicity has now metastasized to the pancreas
causing a decreased output of insulin (66). With insulin
secretion decreased, there is a rapid rise of blood sugar
levels. The development of type 2 diabetes indicates that
the metastasis of silent inflammation from the adipose
tissue to the pancreas is now complete.
Ironically, even extreme lipotoxicity can be reversed
by the creation of new healthy fat cells. This has been
demonstrated in transgenic obese, diabetic mice that
were treated to over-express adiponectin, an adipocytederived hormone that reduces insulin resistance (67). It is
hypothesized that this increased production of adiponectin
activates PPAR gamma, which causes the proliferation
of adipose stem cells to produce new healthy adipocytes.
These transgenetic obese mice become even more obese,
but there is normalization of blood glucose and lipid levels
(67). This is similar to the elevated levels of adiponectin
found in metabolically healthy obese individuals (65).
One mechanism might be that the new healthy fat cells in
the adipose tissue can now sequester circulating AA more
effectively to allow the dissipation of the lipid droplets in
the muscle cells and beta cells of the panaceas. Essentially
this represents a reverse flow of the lipotoxic lipid droplets
in other organs back to the adipose tissue.
Treatments for Obesity and Diabetes

For long-term success in treating obesity and type 2
diabetes, there is no drug intervention that surpasses
gastric bypass surgery in efficacy (68, 69). This is especially
true of Roux-en-Y gastric bypass surgery (70, 71). This
surgery not only causes calorie restriction, but also causes
a significant increase in post-prandial PYY secretion that
is able to maintain satiety with reduced calorie intake
(70,71).
More disturbing is the recent ACCORD study, which
demonstrated that tighter glycemic control in type 2
diabetes appears to result in increased mortality (72). Yet
interestingly, there have been reports that use of highdose anti-inflammatory drugs appear to successfully treat
4

diabetes, and by inference obesity (50). The first of these
reports appeared in 1876 (73), and they continued to
appear several times in the first half of the 20th century
(74, 75). The reduction in elevated blood sugar was almost
immediate. Unfortunately, the treatment of both obesity
and diabetes is life-long therapy and the doses of these
anti-inflammatory drugs required to observe therapeutic
benefits could not be maintained for a lifetime without
adverse side effects. However, these reports do indicate
that an appropriate anti-inflammatory diet might be
constructed that could have similar benefits. That type of
intervention could be maintained for a lifetime.
Anti-Inflammatory Diets
The principal components of a proposed anti-inflammatory
diet should be a low glycemic-load diet, low in omega-6
fatty acids and rich in EPA.
The macronutrient composition of such a diet would
provide about 150 grams of carbohydrate per day. The
majority of carbohydrates should be coming from low
glycemic-load sources that would significantly lower the
production of insulin. This can be achieved by consuming
approximately 10 servings of non-starchy vegetables and
limited amounts of fruits (because of their higher fructose
content) per day with a relatively rigid (but not total)
exclusion of high glycemic-load carbohydrates such as
bread, pasta, rice and potatoes.
The total dietary allotment of only 150 grams of
carbohydrate (600 calories) may initially appear difficult
to achieve considering the abundance of carbohydrates in
the food chain. Yet if one-third of those carbohydrates
(200 calories) came from Mediterranean vegetables, the
individual would have difficulty consuming even this
lowered carbohydrate level because of the caloric volume
of the Mediterranean vegetables. Compliance with
such recommendations can be significantly enhanced
when patients are counseled by telephone to facilitate a
replacement of their current carbohydrates with more
Mediterranean vegetables and fruits (76).
An example of the amounts of different Mediterranean
vegetables that provide 50 calories per day is shown in
Table 1.
Table 1. Mediterranean Vegetables

All of the vegetables listed below are in 50-calorie increments. The
cooked vegetables are steamed and drained. This information is solely
based on the calorie content of the vegetables and does not include oils,
dressings, or other condiments added during the cooking process. The
canned vegetables are not in oil.
RAW VEGETABLES
Broccoli (176g)
Cucumber (402g)
Fennel bulb (161g)
Red/Green Peppers (186g)
Mushrooms (194g)
Onion (133g)
Tomatoes (246g)
Spinach (214g)
Snow Peas (126g)
Zucchini (353g)
Amount for 50 Calories

# of Cups
2 cups chopped
2
2 medium or 3 cups chopped
3
2 cups sliced
2
1 medium or 2 cups sliced
2
1 cup pieces
1
1 medium or cup chopped
2 medium or 2 cups chopped

2
7 cups chopped
3
2 cups whole
2
3 cups sliced
3
COOKED VEGETABLES
Asparagus (203g)
Artichoke (120g)
Broccoli (184g)
Eggplant (177g)
Green Beans (44g)
Kale (180g)
Mushrooms (186g)
Onion (114g)
Red/Green Peppers (270g)
Snow Peas (120g)
Spinach (220g)
Sun-dried Tomato (18g)
Swiss Chard (250g)
Tomato (217g)
Zucchini (310g)

1 cup or 14 spears
1 medium
1 cup chopped
1 cups cubed
1 cup
1 cup chopped
1 cup pieces
cup chopped
2 cups pieces
cup edible peas
1 cup
cup
1 cup chopped
1 cup diced
1 cup sliced
# of Cups
1
1
1
1
1
1
1
1
1
1
CANNED VEGETABLES
Artichoke Hearts (210g)
Capers (225g)
Roasted Red Peppers (280g)

5 pieces
1 cups
2 cups
# of Cups
1
2
The current recommendation of the USDA is for the

consumption of at least 2 cups of vegetables per
day. To meet the goal of consuming 200 calories per
day of Mediterranean vegetables, an individual would
have to consume at least four combinations of the listed
carbohydrate sources (each listed at 50 calories), which
greatly exceeds the recommended USDA amounts of daily

vegetable consumption. Yet that still leaves another 400
calories (100 g) for the consumption of fruits, and limited
amounts of higher glycemic-load carbohydrates so that the
patient is not totally deprived of those carbohydrates hence
ensuring greater long-term compliance.
The protein requirements would be approximately 100
grams of protein per day coming from low-fat sources,
such as fish and chicken or vegetarian protein sources, such
as tofu or imitation soybean meat products. The higher
levels of protein are required to help stimulate the release
of the satiety hormone PYY from the gut (77).
Finally, the fat content would be approximately 50
grams per day. The composition of the fat in an antiinflammatory diet should be low in both omega-6 and
saturated fatty acids. The omega-6 fatty acids provide
the building blocks for increased AA formation and the
resulting elevation of silent inflammation that drives new
fat cell proliferation. Saturated fatty acids are likewise kept
to low amounts since they can activate NF-kappa B via the
TLR4 receptors to cause increased cellular inflammation
(78-82). Thus, the bulk of the dietary fatty acids should
consist of monounsaturated fats, which have virtually
no effect on inflammation. These monounsaturated fats
should also be supplemented by at least 5 grams of longchain omega-3 fatty acids per day. This level of longchain omega-3 fatty acids would increase the secretion of
adiponectin by the fat cells (83-85). Increased adiponectin
production can have significant benefits for reducing
insulin resistance in peripheral tissues (86).
From a macronutrient standpoint, such an antiinflammatory diet could be considered a 1-2-3 diet,
meaning for every one gram of fat consumed, the
individual would consume two grams of protein, and
three grams of carbohydrate. This 1-2-3 ratio stabilizes
postprandial insulin levels, thus relieving the inhibition of
the hormone-sensitive lipase in the fat cells. As a result,
the release of stored fat for ATP production is enhanced.
This 1-2-3 ratio of macronutrients has been examined in
various studies compared to the current macronutrient
recommendations of the USDA, American Heart
Association, and the American Diabetic Association under
isocaloric conditions. In each of these studies, the 1-2-3
ratio has been shown to be superior in reducing hunger
(87,88), reducing insulin and stabilizing blood lipid levels
(89-93), reducing blood glucose levels (94,95), increasing
weight loss in those patients characterized by a high initial
insulin secretion to carbohydrates (96,97), and reducing
silent inflammation (98). The macronutrient composition
of the proposed anti-inflammatory diet is very similar to
that recently proposed by the Joslin Diabetes Research
Center at Harvard Medical School for the treatment of

obesity and type 2 diabetes (99), which is virtually identical
to dietary recommendations that were made more than a
decade ago (100).
Such a macronutrient composition also represents a
calorie-restricted diet providing approximately 1,450
calories per day. It has been demonstrated that this level of
calorie restriction is required to maintain long-term weight
loss (101). Furthermore, Markovic et al has demonstrated
that calorie restriction at 1,200 calories per day can reverse
insulin resistance in type 2 diabetics within four days,
well before any fat loss had occurred (102). One potential
mechanism of this rapid effect of calorie restriction on
insulin resistance may lie in the reduction of the NF-kappa
B activation in hypothalamic neurons (103).
Maintaining such a calorie-restricted diet, however,
depends on controlling hunger primarily by increasing
satiety. This is why an anti-inflammatory diet requires
higher levels of protein (approximately 30% of total
calories) to help stimulate the release of the satiety
hormone PYY from the gut. It has been shown that
increasing PYY levels significantly decreases hunger
(104,105). Furthermore, it has been shown that decreased
post-prandial PYY secretion may be the first indication
of future development of type 2 diabetes well before
the appearance of increased weight or increased insulin
resistance (106,107).
There are additional benefits of the proposed antiinflammatory diet. The first is a significant increase in
the consumption of polyphenols (found in vegetables
and fruits), which are known to have anti-inflammatory
benefits (via the inhibition of NF-kappa B) as well as
activation of AMP kinase to increase the production of
ATP (108-110). Once AMP kinase is activated, then a
number of other metabolic processes that are important
in blood sugar and blood lipid control are also set into
motion (111,112). Activation of AMP kinase is also the
primary mechanism of action for one of the most widely
used diabetic drugs (113). Another benefit of the proposed
anti-inflammatory diet is a decrease in the levels of
endocannabinoids (derived from AA) in the brain, which
play a significant role in hunger development (114).
In many ways, such an anti-inflammatory diet could
be considered similar to the Mediterranean diet with
the following adjustments. The levels of high-glycemic
carbohydrates such as, bread, rice and pasta, are
significantly reduced, replaced by much higher levels of
low-glycemic, non-starchy vegetables and fruits rich in
polyphenols. The primary sources of protein would remain
6

fish and chicken, and the primary fat would still be olive
oil that is low in omega-6 fatty acids. One could consider
the proposed anti-inflammatory diet to be the evolution
of the Mediterranean diet with a far greater reduction in
silent inflammation.
Since the classic Mediterranean diet is associated with a
reduction in the ratio of omega-6 to omega-3 balance in
the blood (115) as well as a decreased incidence of obesity,
diabetes and mortality (116-119), it might be reasonable
to conclude that the proposed anti-inflammatory diet
would have an equal, if not greater, effect in preventing the
development of chronic disease and mortality.
Dietary Reality
Dietary recommendations are one thing, dietary reality
is often another. In fact, it is often said that it is easier
to change ones religion than to change ones diet. The
proposed anti-inflammatory diet, therefore becomes
difficult to implement since it requires a dramatic
reduction in the consumption of bread, pasta, rice, and
other high-glycemic carbohydrates that individuals are
accustomed to consuming.
The solution to this formidable problem requires
manufacturing a new generation of baked products that
not only reduces insulin secretion, but also increases
the release of PYY. To accomplish this requires an
understanding of molecular baking.
Molecular Baking
Molecular baking represents a fusion of material science
technology and food technology. In essence, it treats
proteins, carbohydrates, and fats as polymers that can be
reorganized into different structures that look and taste
like traditional bread, pasta, and rice products. The key
to this technology lies in the development of extensible
dough. This revolutionary new dough consists of protein,
fat, and carbohydrate in a 1-2-3 ratio that can be baked as
a traditional dough, but now imparts a unique variety of
hormonal properties. The first is the reduction of insulin
levels. By reducing the glycemic load flours through the
replacement of carbohydrates with protein, the glycemic
load of the final product is dramatically reduced thereby
reducing insulin secretion. Such products represent lowglycemic versions of the foods that most individuals desire
to eat. Now rather than restricting them from the diet
because of their adverse impact on insulin secretion, their
inclusion in an anti-inflammatory diet provides far greater
7
dietary compliance for the individual since they are eating

the foods they are accustomed to.
More importantly, the process used to make extensible
dough for molecular baking also provides a mechanism
to increase PYY secretion. Normally protein and
carbohydrate are prepared separately, or if combined, they
are kept at low temperatures to prevent extensive crosslinking due to increased temperatures encountered in the
baking process. With extensible dough, this problem
is circumvented as the interaction between protein and
carbohydrates is controlled at the molecular level in the
dough mixing process. As a result, when baked, the
amount of cross-linking is minimized to prevent the
rapid breakdown and absorption of the protein before
it reaches the L-cells in the distal portion of the ileum.
This is important as it is the L-cells in the lower portion
of the gut that release PYY, which goes directly to the
brain to induce satiety. This is exactly the mechanism
for Roux-en-Y gastric bypass surgery. Much of the small
intestine is bypassed, and the limited amount of protein
that can be absorbed (due to the reduction of the stomach
size) is delivered in high amounts directly to the L-cells.
This is why the first thing that the gastric bypass patient
experiences after surgery is an almost immediate lack of
hunger, often for the first time in their lives. Products
made using extensible dough can deliver many of the same
hormonal benefits as gastric bypass surgery. This is because
more of the dietary protein is delivered to the L-cells since
the rate of digestion and absorption of protein in the upper
section of the gut has been reduced due to the controlled
cross-linking of the protein and carbohydrate during the
baking process.
With the advent of molecular baking, it becomes much
easier for the individual to maintain an anti-inflammatory
diet since breads and pasta become an integral part of their
dietary success to increase satiety. It should be kept in
mind that the 1-2-3 macronutrient balance is still necessary
to control insulin as this is critical for the relaxation of the
fat trap, thus allowing more stored fat to be released into
the circulation for increased ATP production. Keep in
mind without the use of bread and pasta products made
with the new extensible dough technology, the stimulation
of PYY secretion will still be compromised regardless of
how well the 1-2-3 macronutrient balance is maintained by
the individual.
Pilot studies we have conducted indicate that
approximately 1,000 calories per day of extensible dough
products delivered in three meals and two snacks are
sufficient to maintain high levels of satiety. This allows for
another 500 calories per day for additional low-glycemic

carbohydrates, such as non-starchy vegetables and limited
amounts of fruits that are rich in polyphenols. However, it
must be remembered that it is the increased PYY secretion
that makes it possible to maintain a calorie-restricted
dietary program indefinitely.
11. Martinelli N, Girelli D,Malerba G, Guarini P, Illig T, Trabetti

E,Sandri M, Friso S, Pizzolo F, Schaeffer L, Heinrich J,
Pignatti PF, Corrocher R, Olivieri O: FADS genotypes and
desaturase activity estimated by the ratio of arachidonic acid
to linoleic acid are associated with inflammation and coronary
artery disease. Am J Clin Nutr 88: 941-949, 2008
Summary
12. Darmon N, Darmon M, Maillot M, Drewnowski A: A

nutrient density standard for vegetables and fruits: nutrients
per calorie and nutrients per unit cost. J Am Diet Assoc
105:1881-1887, 2005
Obesity and type 2 diabetes are inflammatory conditions

that should be successfully treated by anti-inflammatory
interventions. One such intervention is the long-term
use of a proposed anti-inflammatory diet that delivers the
benefits of calorie-restriction and hormonal modulation
that currently can only be achieved with gastric bypass
surgery. This is especially true if that anti-inflammatory
diet makes extensive use of products produced by
molecular baking.
References
1.
Hossain P. Kawar B, Nahas ME: Obesity and diabetes in the

developing world. N Engl J Med 356:213-216, 2007
2.
Sears B. The OmegaRx Zone. New York:Regan Books, 2002
3.
Sears B. The Anti-Inflammation Zone. New York:Regan

Books, 2005
4.
Sears B. Toxic Fat. Nashville:Thomas Nelson, 2008
5. Tall AR: C-reactive protein reassessed. N Engl J Med

350:1450-1452, 2004
6.
Campbell B, Badrick T, Flatman R, Kanowshi D: Limited

clinical utility of high-sensitivity plasma C-reactive protein
assays. Ann Clin Biochem39:85-88, 2002
7. Campbell B, Flatman R, Badrick T, Kanowshi D: Problems

with high-sensitivity C-reactive protein. Clin Chem 49:201,
2003
8.
Drewnowski A,Specter SE. Poverty and obesity: the role of

energy density and energy costs. Am J Clin Nutr 79:6-16,
2004
9. Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden

H, Baldwin JM, Bowling AC, Newman HC, Jenkins AL,
Goff DV: Glycemic index of foods: a physiological basis for
carbohydrate exchange. Am J Clin Nutr 34:362-366, 1981
10. Ludwig DS: The glycemic index: physiological mechanisms
relating to obesity, diabetes, and cardiovascular disease. JAMA
287:2414-2423,2002
13. Drewnowski A, Darmon N, Briend A: Replacing fats and

sweets with vegetables and fruits--a question of cost. Am J
Public Health 94: 1555-1559, 2004
14. Monsivais P, Drewnowski A: The rising cost of low-energydensity foods. J Am Diet Assoc 107:2071-2076, 2007
15. Brenner RR: Nutrition and hormonal factors influencing
desaturation of essential fatty acids. Prog Lipid Res 20:41-48,
1982
16. el Boustani S, Gausse JE, descomps B, Monnier L, Mendy
F, Crastes de Paulet A: Direct in vivo characterization of the
delta-5 desaturase activity in humans by deuterium labeling:
effect of insulin. Metab 38:315-3321, 1989
17. Pelikonova T, Kohout M, Base J, Stefka Z, Kovar L, Kerdova
L, Valek J: Effect of acute hyperinsulinemia on fatty acid
composition of serum lipid in non-insulin dependent diabetics
and healthy men. Clin Chem Acta 203:329-337, 1991
18. Brenner RR: Hormonal modulation of delta-6 and delta-5
desaturases. Prostaglandins Leukot Essent Fatty Acids 68:151162, 2003
19. Serhan CN, Hong S, Gronert K, Colgan SP, Devchand PR,
Mirick G, Moussignac RL: Resolvins: a family of bioactive
products of omega-3 fatty acid transformation circuits initiated
by aspirin treatment that counter proinflammation signals. J
Exp Med 196:1025-1037, 2002
20. Serhan CN, Arita M, Hong S, Gotlinger K: Resolvins,
docosatrienes, and neuroprotectins, novel omega-3-derived
mediators, and their endogenous aspirin-triggered epimers.
Lipids 39:1125-1132, 2004
21. Serhan CN: Novel omega-3 derived local mediators in antiinflammation and resolution. Pharmacol and Therapeutics
105:7-21, 2005
22. Serhan CN: Resolution phase of inflammation: novel
endogenous anti-inflammatory and proresolving lipid
mediators and pathways. Annu Rev Immunol 25:101-137,
2007

23. Simopoulos AP: Essential fatty acids in health and chronic
disease. Am J Clin Nutr 70:560S-569S, 1999
36. Taubes G: Good Calories, Bad Calories. New York:Alfred

Knopf, 2007
24. Massiera F, Saint-Marc P, Sedoux J, Murata T, Kobayshi T,

Marumiya S, Guesnet P, Amri, E-Z, Megrel R, Ailhaud G:
Arachidonic acid and prostacylin signaling promote adipose
tissue development: a human health concern? J Lipid Res
44:271-279, 2003
37. van den Hoek AM, Teusink B, Voshol PJ, Havekes LM,
Romijin JA, Pijl H: Leptin deficiency per se dictates
body composition and insulin action in ob/ob mice. J
Neuroendocrinology 20:120-127, 2008
25 Mazid MA, Chowdhury AA, Nagao K, Nishimura K, Jisaka

M, Nagaya T, Yokota K: Endogenous 15-deoxy-delta(12,14)prostaglandin J(2) synthesized by adipocytes during maturation
phase contributes to upregulation of fat storage. FEBS Lett
580:6885-6890, 2006
26. Savva SC, Chadjigeorgiou C, Hatzis C, Kyriakakis M,
Tsimbinos G, Tornaritis M, Kafatos A: Association of adipose
tissue arachidonic acid content with BMI and overweight
status in children from Cyprus and Crete. Br J Nutr 91: 643649, 2004
27. Hollenbeck C, Reaven GM: Variations in insulin-stimulated
glucose uptake in healthy individuals with normal glucose
tolerance. J Clin Endocrinol Metab. 64:1169-1173, 1987
28 National Center for Health Statistics: Health, United States,
2007, 2007
38. Kotidis EV, Koliakos GG, Baltzopoulos VG, Ioannidis KN,

Yovos JG, Papavramidis ST: Serum ghrelin, leptin and
adiponectin levels before and after weight loss: comparison of
three methods of treatment--a prospective study. Obes Surg
16:1425-1432, 2006
39. Santosa S, Demonty I Lichtenstein AH Cianflone K, Jones
PJ: An investigation of hormone and lipid associations after
weight loss in women. J Am Coll Nutr 26:250-258, 2007
40. Williams ES, Baylin A, Campos H: Adipose tissue arachidonic
acid and the metabolic syndrome in Costa Rican adults. Clin
Nutr 26:474-482, 2007
41. Aldamiz-Echevarria L, Prieto JA, Andrade F, Elorz J, Sanjurjo
P, Rodriguez Soriano J: Arachidonic acid content in adipose
tissue is associated with insulin resistance in healthy children. J
Pediatr Gastroenterol Nutr 44:77-83, 2007
29. Maeda K, Uysal KT, Makowski L, Gorgun CZ, Atsumi G,

Parker RA, Bruning J, Hertzel AV, Bernlohr DA, Hotamisligil
GS: Role of the fatty acid binding protein mal1 in obesity and
insulin resistance. Diabetes 52:300-307, 2003
42. McLaughlin T, Sherman A, Tsao P, Gonzalez O, Yee G,

Lamendola C, Reaven GM, Cushman SW: Enhanced
proportion of small adipose cells in insulin-resistant vs. insulinsensitive obese individuals implicates impaired adipogenesis.
Diabetologia 50:1707-1715, 2007
30. Bonen A, Tandon NN, Glatz JFC, Luiken JJFP, Heigenhauser

GJF: The fatty acid transporter FAT/CD36 is upregulated in
subcutaneous and visceral adipose tissues in human obesity and
type 2 diabetes. Int J Obesity 30:877-883, 2006
43. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel

RL, Ferrante AW: Obesity is associated with macrophage
accumulation in adipose tissue. J Clin Invest 112:1796-1808,
2003
31 Erbay E, Cao H, Hotamisligil GS: Adipocyte/macrophage

fatty acid binding proteins in metabolic syndrome. Curr
Atheroscler Rep 9:222-2229, 2007
44. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole

J, Nichols A, Ross JS, Tartaglia LA, Chen H: Chronic
inflammation in fat plays a crucial role in the development
of obesity-related insulin resistance. J Clin Invest 112:18211830, 2003
32. Duruhashi M, Fucho R, Gorgun CZ, Tuncman G, Cao H,

Hotamisligil GS: Adipocyte/macrophage fatty acid binding
proteins contribute to metabolic deterioration through actions
in macrophages and adipocytes in mice. J Clin Invest 118:
2640-2650, 2008
33 Botion LM, Green A: Long-term regulation of lipolysis and
hormone-sensitive lipase by insulin and glucose. Diabetes
48:1691-1697, 1999
34. Haemmerle G, Zimmermann R, Zechner R: Letting lipids go:
hormone-sensitive lipase. Cur Opin Lipidol 14:289-297, 2003
35. Yeaman SJ: Hormone-sensitive lipase--new roles for an old
enzyme. Biochem 379:11-22, 2004
45. Wellen KE, Hotamisligil GS: Obesity-induced inflammatory

changes in adipose tissue. J Clin Invest 112:1785-1788, 2003
46. Festa A, DAgostino R, Howard G, Mykkanen L, Tracy RP,
Haffner SM: Chronic subclinical inflammation as part of the
insulin resistance syndrome. Circulation 102:42-47, 2000
47. Ruan H, Lodish HF: Insulin resistance in adipose tissue: direct
and indirect effects of tumor necrosis factor-alpha. Cytokine
Growth Factor Rev 14:447-455, 2003

48. Pompeia C, Lima T, Curi R: Arachidonic acid cytotoxicity:
can arachidonic acid be a physiological mediator of cell death?
Cell Biochem Funct 21:97-104, 2003
49. Permana PA, Menge C, Reaven PD: Macrophage-secreted
factors induce adipocyte inflammation and insulin resistance.
Biochem Biophys Res Commun 341:507-514, 2006
60. Huber J, Loffler M, Bilban M, Reimers M, Kadl A, Todoric J,

Zeyda M, Geyeregger R, Schreiner M, Weichhart T, Leitinger
N, Waldhausl W, Stulnig TM: Prevention of high-fat dietinduced adipose tissue remodeling in obese diabetic mice by
n-3 polyunsaturated fatty acids. Int J Obes 31:1004-1013,
2007
50. Shoelson SE, Lee J, Goldfine AB: Inflammation and insulin

resistance. J Clin Invest 116:1793-1801, 2006
61. Unger RH: Weapons of lean body mass destruction: the role
of ectopic lipids in the metabolic syndrome. Endocrinology
144:5159-5165, 2003
51. Neels JG, Olefsky JM: Inflamed fat: what starts the fire? J Clin
Invest 116:33-35, 2006
62. Unger RH: Lipotoxic diseases. Ann Rev Med 53:319-336,

2002
52. Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia

E, Wang S, Fortier M, Greenberg AS, Obin MS: Adipocyte
death defines macrophage localization and function in adipose
tissue of obese mice and humans. J Lipid Res 46:2347-2355,
2005
63. Wildman RP,Muntner P, Reynolds K, McGinn AP,

Rajpathak S, Wylie-Rosett J, Sowers MR: The obese without
cardiometabolic risk factor clustering and the normal weight
with cardiometabolic risk factor clustering: prevalence
and correlates of 2 phenotypes among the US population
(NHANES 1999-2004). Arch Intern Med 168:1617-1624,
2008
53. Lee YH and Pratley RE. The evolving role of inflammation in

obesity and the metabolic syndrome. Curr Diab Rep 5:70-75
(2005)
54. Yudkin JS: Inflammation, obesity, and the metabolic
syndrome. Horm Metab Res 39:707-709, 2007
55. Heilbronn LK, Campbell LV: Adipose tissue macrophages,
low-grade inflammation and insulin resistance in human
obesity. Curr Pharm Des 14: 1225-1230, 2008
56. de Luca C, Olefsky JM: Inflammation and insulin resistance.
FEBS Letters 582:97-105, 2008
57. Kinstcher U, Hartge M, Hess K, Foryst-Ludwig A, Cleminz
M, Wabitsch M, Fischer-Posovszky P, Barth TF, Dragun
D, Skurk T, Hauner H, Bluher M, Unger T, Wolf AM,
Knippschild U, Homback V, Marx N: T-lymphocyte
infiltration in visceral adipose tissue: a primary event in adipose
tissue inflammation and the development of obesity-mediated
insulin resistance. Arterioscler Thromb Vasc Biol 28:13041310, 2008
58. Kahn S, Hull RL, Utzschneider KM: Mechanisms linking
obesity to insulin resistance and type 2 diabetes. Nature
444:840-846, 2007
59. Todoric J, Lffler M, Huber J, Bilban M, Reimers M, Kadl
A, Zeyda M, Waldhusl W, Stulnig TM: Adipose tissue
inflammation induced by high-fat diet in obese diabetic mice
is prevented by n-3 polyunsaturated fatty acids. Diabetologia
49:2109-2119, 2006
64. Karelis AD, Faraj M, Bastard JP, St-Pierre DH, Brochu M,

Prudhomme D, Rabasa-Lhoret R. The metabolically healthy
but obese individual presents a favorable inflammation profile.
J Clin Endocrinol Metab. 90:4145-4150, 2005
65. Aguilar-Salinas CA Garcia EG Robles L Riano D RuizGomez DG Garcia-Ulloa AC, Melgarejo MA, Zamora M,
Guillen-Pineda LE, Mehta R, Canizales-Quinteros S, Tusie
Luna MT, Gomez-Perez FJ: High adiponectin concentrations
are associated with the metabolically healthy obese phenotype.
J Clin Endocrinol Metab 93:4075-4079, 2008
66. Unger RH, Zhou YT: Lipotoxicity of beta-cells in obesity and
in other causes of fatty acid spillover. Diabetes 50:S118-121,
2001
67. Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME,
Hofmann SM, Schraw T, Durand JL, Li H, Li G, Jelicks LA;
Mehler MF, Hui DY, Deshaies Y, Shulman GI, Schwartz GJ,
Scherer PE: Obesity-associated improvements in metabolic
profile through expansion of adipose tissue. J Clin Invest
117:2621-2637, 2007
68. Levy P, Fried M, Santini F, Finer N: The comparative effects
of bariatric surgery on weight and type 2 diabetes. Obes Surg
17:1248-1256, 2007
10

69. Sjostrom L, Narbro K, Sjostrom CD, Karason K,Larsson B,
Wedel H, Lystig T, Sullivan M, Bouchard C, Carlsson B,
Bengtsson C, Dahlgren S, Gummesson A, Jacobson P, Karlsson
J, Lindroos AK, Lonroth H,Naslund I, Olbers T, Stenlof
K, Torgerson J, Agren G, Carlsson LM: Effects of bariatric
surgery on mortality in Swedish obese subjects. N Engl J Med
357:741-752, 2007
70. le Roux CW, Welbourn R, Werling M, Osborne A, Kokkinos
A, Laurenius A, Lonroth H, Fandriks L, Ghatei MA, Bloom
SR, Olbers T: Gut hormones as mediators of appetite and
weight loss after Roux-en-Y gastric bypass. Ann Surg 246:780785, 2007
71. le Roux CW, Aylwin SJ, Batterham RL, Borg CM, Coyle F,
Prasad V, Shurey S, Ghatei MA, Patel AG, Bloom SR: Gut
hormone profiles following bariatric surgery favor an anorectic
state, facilitate weigh loss, and improve metabolic parameters.
Ann Surg 243:108-114, 2006
72. Action to Control Cardiovascular Risk in Diabetes Study
Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr,
Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F,
Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald
WT: Effects of intensive glucose lowering in type 2 diabetes.
N Engl J Med. 358:2545-2559, 2008
73. Ebstein W: Zur therapie des diabetes mellitus, insbesondere
ber die anwendung des salicylsauren natron bei demselben.
Berliner Klinische Wochenschrift. 13: 337340, 1876
74. Williamson RT: On the treatment of glycosuria and diabetes
mellitus with sodium salicylate. Br Med J i:760762, 1901
75. Reid J, MacDougall AI, Andrews MM: On the efficacy of
salicylate in treating diabetes mellitus. Br Med J ii:10711074,
1957
76. Djuric Z, Vanloon G, Radakovich K, Dilaura NM, Heibrun
LK, Sen A: Design of a Mediterranean exchange list diet
implemented by telephone counseling. J Am Diet Assoc
108:2059-2065, 2008
77. Batterham RL, Heffron H, Kapoor, S, Chivers, JE,
Chandarana K, Herzog H, le Roux CW, Thomas EL, Bell JD,
Withers DJ: Critical role for peptide YY in protein-mediated
satiation and body-weight regulation. Cell Metab 4:223-233,
2006
78. Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, Sizemore N,
Hwang DH: Reciprocal modulation of Toll-like receptor-4
signaling pathways involving MyD88 and phosphatidylinositol
3-kinase/AKT by saturated and polyunsaturated fatty acids. J
Biol Chem 278:37041-37051, 2003
11
79. Lee JY, Zhao L, Youn HS, Weatherill AR, Tapping R, Feng
L, Lee WH, Fitzgerald KA, Hwang DH: Saturated fatty
acid activates but polyunsaturated fatty acid inhibits Toll-like
receptor 2 dimerized with Toll-like receptor 6 or 1.
J Biol Chem 279:16971-16799, 2004
80. Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X,
Mizuarai S, Kotani H, Yamaoka S, Miyake K, Aoe S, Kamei Y,
Ogawa Y: Role of the Toll-like receptor 4/NF-kappaB pathway
in saturated fatty acid-induced inflammatory changes in the
interaction between adipocytes and macrophages. Arterioscler
Thromb Vasc Biol 27:84-91, 2007
81. Kennedy A, Marinez K, chuang C-C, LaPoint K, McIntosh
M: Saturated fatty acid-mediated inflammation and insulin
resistance in the adipose tissue. J Nutr 139:1-4, 2009
82. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS.
TLR 4 links innate immunity and fatty acid-induced insulin
resistance. J Clin Invest 116:3015-3025, 2006
83. Neschen S, Morino K, Rossbacher JC, Pongratz RL, Cline
GW, Sono S, Gillum M, Shulman GI: Fish oil regulates
adiponectin secretion by a peroxisome proliferator-activated
receptor-gamma-dependent mechanism in mice. Diabetes
55:924-928, 2006
84. Itoh M, Suganami T, Satoh N, Tanimoto-Koyama K, Yuan X,
Tanaka M, Kawano H, Yano T, Aoe S, Takeya M, Shimatsu A,
Kuzuya H, Kamei Y, Ogawa Y: Increased adiponectin secretion
by highly purified eicosapentaenoic acid in rodent models of
obesity and human obese subjects. Arterioscler Thromb Vasc
Biol 27:1918-1925, 2007
85. Ramel A, Marinez A, Kiely M, Morais G, Bandarra NM,
Thordottir I: Beneficial effects of long-chain n-3 fatty acids
included in an energy-restricted diet on insulin resistance in
overweight and obese European young adults. Diabetologia
51:1261-1268, 2008
86. Lu JY, Huang KC, Chang LC, Huang YS, Chi YC, Su TC,
Chen CL, Yang WS: Adiponectin: a biomarker of obesityinduced insulin resistance in adipose tissue and beyond. J
Biomed Sci 15:565-576, 2008
87. Ludwig DS, Majzoub JA, Al-Zahrani A, Dallal GE, Blanco,
Roberts SB, Agus MS, Swain JF, Larson CL, Eckert EA:
Dietary high-glycemic index foods, overeating, and obesity.
Pediatrics 103: E26, 1999
88. Agus MS, Swain JF, Larson CL, Eckert EA, Ludwig DS:
Dietary composition and physiological adaptation to energy
restriction. Am J Clin Nutr 71:901-907, 2000

89. Dunesnil JG, Turgeon J, Tremblay A, Poirer P, Gilbert M,
Gagnon L, St-Pierre S, kGarneau C, Lemieux I, Pascot A,
Bergeron J, Despres JP: Effect of a low-glycaemic indexlowfathigh-protein diet on the atherogenic metabolic risk profile
of abdominally obese men. Br J Nutr 86:557-568, 2001
90. Layman DK, Shiue H, Sather C, Erickson DJ, Baum
J: Increased dietary protein modifies glucose and insulin
homeostasis in adult women during weight loss. J Nutr
133:405-410, 2003
91. Layman DK, Boileau RA, Erickson DJ, Painter JE, Shiue
H, Sather C, Christou DD: A reduced ratio of dietary
carbohydrate to protein improves body composition and
blood lipid profiles during weight loss in adult women. J Nutr
133:411-417, 2003
92. Wolfe BM, Piche LA: Replacement of carbohydrate by protein
in a conventional-fat diet reduces cholesterol and triglyceride
concentrations in healthy normolipidemic subjects. Clin
Invest Med 22:140-148, 1999
93. Fontani G, Corradeschi F, Felici A, Alfatti F, Bugarini R,
Fiaschi AI, Cerretani D, Montorfano G, Rizzo AM, Berra B:
Blood profiles, body fat and mood state in healthy subjects on
different diets supplemented with omega-3 polyunsaturated
fatty acids. Eur J Clin Invest 35:499-507, 2005
100. Sears B. The Zone. New York:Regan Books, 1995

101. Wing RR, Hill JO: Successful weight loss maintenance. Ann
Rev Nutr 21:323-341, 2001
102. Markovic TP, Jenkins AB, Campbell LV, Furler SM, Kraegen
EW, Chishol DJ: Determinants of glycemic responses to diet
restriction and weight loss in obesity and NIDDM. Diabetes
Care 21:687-694, 1998
103. Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai
D: Hypothalamic IKKB/NK-kappa B and ER stress link
overnutrition to energy imbalance and obesity. Cell 135:6173, 2008
104. le Roux CW, Batterham RL, Aylwin SJB, Patterson M, Borg
CM, Wynne KJ, Ken A, Vencent RP, Cardiner J, Chatei MA,
Bloom SR: Attenuated peptide YY release in obese subjects is
associated with reduce satiety. Endocrinology 147:3-8, 2006
105. Young AA: Obesity: a peptide YY-deficient, not peptide YYresistant, state. Endocrinology 147:1-2, 2006
106. Boey D, Heibronn L, Sanisbury A, Laybutt R, Kriketos A,
Herzog H, Campbell LV: Low serum PYY is linked to insulin
resistance in first-degree relatives of subjects with type 2
diabetes. Neuropeptides 40:317-324, 2006
94. Nuttall FQ, Gannon MC, Saeed A, Jordan K, Hoover H: The

metabolic response of subjects with type 2 diabetes to a highprotein, weight-maintenance diet. J Clin Endocrinol Metab
2003 88:3577-3583, 2003
107. Viardot A, Heilbronn LK, Herzog H, Gregersen S, Campbell

LV: Abnormal postprandial PYY responses in insulin sensitive
nondiabetic subjects with a strong family history of type 2
diabetes. Int J Obesity 32:943-948, 2008
95. Gannon MC, Nuttall FQ, Saeed A, Jordan K, Hoover H. An

increase in dietary protein improves the blood glucose response
in persons with type 2 diabetes. Am J Clin Nutr 78:734-741,
2003
108. Yoon JH, Baek SJ: Molecular targets of dietary polyphenols

with anti-inflammatory properties. Yonsei Med J 46:585-596,
2005
96. Ebbeling CB, Leidig MM, Feldman HA, Lovesky MM,

Ludwig DS: Effects of a low-glycemic load vs low-fat diet in
obese young adults: a randomized trial. JAMA 297:2092-2102,
2007
97. Pittas AG, Das SK, Hajduk CL, Golden J, Saltzman E, Stark
PC, Greenberg AS, Roberts SB: A low-glycemic load diet
facilitates greater weight loss in overweight adults with high
insulin secretion but not in overweight adults with low insulin
secretion in the CALERIE Trial. Diabetes Care 28:2939-2941,
2005
98. Pereira MA, Swain J, Goldfine AB, Rifai N, Ludwig
DS: Effects of a low-glycemic load diet on resting energy
expenditure and heart disease risk factors during weight loss.
JAMA 292:2482-2490, 2004
99. Joslin Diabetes Research Center Dietary Guidelines. www.
joslin.org/Files/Nutrition_Guideline_Graded.pdf
109. Scalbert A, Johnson IT, Saltmarsh M: Polyphenols:

antioxidants and beyond. Am J Clin Nutr 81:215S-217S,
2005
110. Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X,
Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA: Polyphenols
stimulate AMP-activated protein kinase, lower lipids, and
inhibit accelerated atherosclerosis in diabetic LDL receptordeficient mice. Diabetes 55:2180-2191, 2006
111. Viollet B, Mounier R, Leclerc J, Yazigi A, Foretz M, Andreelli
F: Targeting AMP-activated protein kinase as a novel
therapeutic approach for the treatment of metabolic disorders.
Diabetes Metab 33:395-402, 2007
112. Winder WW, Thomson DM: Cellular energy sensing and
signaling by AMP-activated protein kinase. Cell Biochem
Biophys 47:332-347, 2007
12

113. Zou MH, Kirkpatrick SS, Davis BJ,Nelson JS, Wiles WG,
Schlattner U, Neumann D, Brownlee M, Freeman MB,
Goldman MH: Activation of the AMP-activated protein
kinase by the anti-diabetic drug metformin in vivo. Role
of mitochondrial reactive nitrogen species. J Biol Chem
279:43940-43951, 2004
114. Watanabe S, Doshi M, Hamazaki T: n-3 polyunsaturated
fatty acid (PUFA) deficiency elevates and n-3 PUFA
enrichment reduces brain 2-arachidonylglycerol level in mice.
Prostaglandins Leukot Essent Fatty Acids 69:51-59, 2003
115. Ambring A, Johansson M, Axelsen M, Gan L, Strandvik B,
Friberg P: Mediterranean-inspired diet lowers the ratio of
serum phospholipids n-6 to n-3 fatty acids, the number of
leukocytes and platelets, and vascular endothelial growth factor
in healthy subjects. Am J Clin Nutr 83:575-581, 2006
116. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D:
Adhereence to a Mediterranean diet and surivival in a Greek
population. N Engl J Med 348:2599-2608, 2003
117. Vioque J, Weinbrenner T, Castello A, Asensio L, Garcia de la
Hera M: Intake of fruits and vegetables in relation to 10-year
weight gain among Spanish adults. Obesity 16:664-670, 2008
118. Martinez-Gonzalez MA, de la Fuente-Arrillage C, Nunezcordoba JM, Basterra-Gortari FJ, Beunza JJ, Vazquez Z, benito
S, Tortosa A, Bes-Rastrollo M: Adherence to Mediterranean
diet and risk of developing diabetes: prospective cohort study.
Br Med J 336:1348-1351, 2008
119. Mitrou PN, Kipnis V, Thiebaut AC, Reedy J, Subar AF,
Wirfalt E, Flood A, Mouw T, Hollenbeck AR, Leitzmann MF,
Schatzkin A: Mediterranean dietary pattern and prediction of
all-cause mortality in a US population: results from the NIHAARP Diet and Health Study. Arch Intern Med 167:24612468, 2007
13
The Inflammation Research Foundation

is a non-profit 501(c) corporation whose
mission includes physician education on the
potential of anti-inflammatory medicine
and sponsorship of clinical trials using antiinflammatory diets in the treatment of a
variety of chronic disease conditions.
Copyright 2009 Inflammation Research Foundation
14

21 Tioga Way, Marblehead, MA 01945
Tel: 781-639-1214 Fax: 781-639-8154
www.inflammationresearchfoundation.org

Anti-Inflammatory Medicine - Barry Sears

Загружено:

Сведения о документе

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Anti-Inflammatory Medicine - Barry Sears

Загружено:

Авторское право:

Доступные форматы

Anti-Inflammatory Medicine:

Dietary Modulation of Eicosanoids

Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids

2.1 Types of inflammation .................................................................................

3.0 Dietary influences on eicosanoids . ............................................................. 4

3.1 Evolution of the nutrition and the immune response ....................................

4.0 What is the Zone? .......................................................................................... 6

4.1 What is an anti-inflammatory diet? . ........................................................... 6

5.0 Other Physiological Effects of Omega-3 Fatty Acids ................................. 7

12.1 Levels of omega-3 fatty acids required ........................................................ 9

13.0 Conclusions ................................................................................................. 10

Inflammation Research Foundation

or heal injuries. Too much of an inflammatory response, and

2.1 Types of inflammation

2.2 Mediators of inflammation

2.3 Clinical markers of inflammation

Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids

2.4 Defining Wellness

Inflammation Research Foundation

3.2 What are Eicosanoids?

Prevent blood clots caused by

Promote blood clots caused

Decrease cell division

Promote cell division

Enhance the immune system

Depress the immune system

3.3 Essential fatty acids and eicosanoids

Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids

Inhibited by Trans Fatty Acids and DHA

Gamma linolenic acid (GLA)

4.1 What is an anti-inflammatory diet?

Inhibited by Glucagon and EPA

Arachidonic Acid (AA)

3.4 Drugs that alter eicosanoids

Inflammation Research Foundation

4.2 Clinical markers of the Zone

Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids

Results of the GISSI Study

7.0 Eicosanoids and Neurological Disease

Cardiovascular mortality -20%

8.0 Eicosanoids and Cancer

Inflammation Research Foundation

12.1 Levels of EPA and DHA required

EPA and DHA

12.2 Fish Oil Purity

12.3 Problems with Fish Oil

Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids

EPA and DHA. At higher doses of aspirin, this effect on making

Inflammation Research Foundation

13. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y,

9. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir

19. Tchernof A, Lamarche B, PrudHomme D, Nadeau A,

10. Yamada T, Strong JP, Ishii T, Ueno T, Koyama M, Wagayama

20. Jeppesen J, Hein HO, Suadicani P, and Gyntelber, F. Low

11. Nakamura T, Takebe K, Tando Y, Arai Y, Yamada N, Ishii M,

21. Hotamisligil GS. Inflammation and metabolic disorders.

Anti-Inflammatory Medicine: Dietary Modulation of Eicosanoids

36. Neschen S, Morino K, Dong J, Wang-Fischer Y, Cline GW,

Inflammation Research Foundation

48. Stoll AL, Sverus E, Freeman MP, Rueter S, Zhoyan HA,

39. Gaziano JM, Skerrett PJ, and Buring JE. Aspirin in

50. Nordvik I, Myhr K-M, Nyland H, and Bjerve KS. Effect of

40. Lamarche B, Lemieux I, and Despres JP. The small dense

51. Maes M. Fatty acid composition in major depression: