Intricacies of Fat Lisa Stehno-Bittel PHYS THER. 2008; 88:1265-1278.

Originally published online September 18, 2008 doi: 10.2522/ptj.20080034

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Diabetes Special Issue

Intricacies of Fat
Lisa Stehno-Bittel One of the most exciting cell biology elds of study concerns the physiology and pathology of fat. The basic assumptions once held concerning the function of adipose tissue have been shown to be oversimplied or sometimes completely wrong. Fat does more than store excess energy; it is actually the largest endocrine organ in the body, and it may be one of the most active. Adipocytes release hormones and other molecules that act on nearby tissues and travel through the vasculature to distant sites, such as the brain, skeletal muscle, and liver. Under conditions of normal weight, those signals help the body to suppress hunger, utilize glucose, and decrease the risk of cardiovascular disease. However, under conditions of obesity, the hormones (or the proteins that bind the hormones) become abnormal and can result in states of chronic inammation leading to diabetes and heart disease. In addition, excessive fat can lead to the accumulation of lipid droplets in nonfat cells, including skeletal and cardiac muscle. Although some lipid droplets are used as an immediate source of energy for cells, large numbers of stored droplets can cause cellular damage and cell death. The purposes of this article are to review the normal and deviant signals released by fat cells, to draw a link between those signals and chronic diseases such as diabetes, and to discuss the role of exercise in reversing some of the deviant signaling perpetrated by excess fat.
L Stehno-Bittel, PT, PhD, is Professor and Chair, Department of Physical Therapy and Rehabilitation Science, and Scientic Director, Great Plains Diabetes Institute, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160 (USA). Address all correspondence to Dr StehnoBittel at: LBITTEL@kumc.edu. [Stehno-Bittel L. Intricacies of fat. Phys Ther. 2008;88:12651278.] 2008 American Physical Therapy Association

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Intricacies of Fat

t is no surprise that excess adipose tissue is unhealthful. Even before scientic data explained the pathological consequences of excessive weight gain, it was intuitively known that being overweight was not healthful. The newsworthy information includes the expansive multitude of negative effects caused by excessive fat and the elaborate mechanisms that fat uses to do its damage. The prevailing thought for decades was that fat was a passive site in the body for energy storage. When people eat more calories than they use, the excess is stored in fat cells as triglycerides. Conversely, when the body is lacking calories in relation to the energy expended, fatty acids are released by fat cells. Other prevalent beliefs were that all people were born with a certain number of fat cells and that number was stable across the life span. People were believed to gain weight through hypertrophy or expansion of individual cells, not through an increase in the number of fat cells. Loss of weight was believed to occur through a decrease in the size of fat cells, not through a reduction in the total number of cells.1

cytes release aberrant factors that can cause or amplify metabolic disorders. Thus, adipose tissue itself plays a role in causing diseases such as type 2 diabetes and cardiovascular disease. In addition to its endocrine function, fat serves as an immune organ. Some researchers2 argue that fat may be predominantly an immune organ. The link between obesity and atherosclerosis and other vascular diseases may lie in the immune function of adipocytes, which is reviewed later in this article. In people who are healthy and of normal weight, fat cells release molecules that regulate blood pressure, blood coagulation, and estrogen release in postmenopausal women, among other things.3 (Also see the related article by Cade4 on microvascular and macrovascular disease in diabetes mellitus in this issue.) It is now known not only that fat is more than a storage site for excess energy but also that obesity is both an enlargement of adipocytes and an increase in the number of adipocytes formed from a large pool of precursor stem cells.5 Large fat cells are less sensitive to insulin and exert a higher basal rate of lipolysis, the release of free fatty acids by adipocytes, than small fat cells.6 Adipokines are molecules released by fat cells that in many instances cause the pathological conditions associated with obesity. The question is: Why would evolution lead humans to a situation in which excessive obesity is encouraged or enhanced by factors that induce chronic inammation and send aberrant signals to the brain and muscle? In order to answer that question, one must imagine what life was like for thousands of years when all creatures had to exist off the land in uctuating states of feast or famine. When food was scarce, the body

used its reserves to exist. When food was in abundance, the body released specic molecules (many of them adipokines) to induce fat formation and decrease glucose utilization in the form of short-term insulin resistance.7 The energy stored in the fat could be called upon in future times of famine. Insulin resistance was meant to be a temporary state when food was abundant. Most people in the United States no longer live in a world in which food is ever scarce. Therefore, what had at one time been a benecial adaptation that promoted survival has now become a curse for the 66% of all American adults who are overweight or obese.8 No wonder gaining weight is so easy and losing weight is so difcult: People are genetically programmed to accumulate fat in times of food abundance. The once temporary state of insulin resistance meant to help the species survive has now become the permanent state of type 2 diabetes. This explanation for the high levels of worldwide obesity was rst proposed over 40 years ago and was termed the thrifty genotype.9 One problem with the thrifty gene theory in explaining the current obesity epidemic is that it predicts that every person with an ample food supply should be obese; although that is certainly the trend,10 it is not universal. Alternative hypotheses rely on random genetic drift, as opposed to directed selection of survival genes, to explain the worldwide health care crisis of obesity.11

Over time, an entirely new understanding of fat has emerged, and what researchers were sure they understood about fat only a few years ago was found to be incomplete or sometimes entirely wrong. Research over the past 10 years has dramatically changed the view of fat. Fat is now classied as an endocrine organ. In fact, it is the largest endocrine organ in the body. Adipocytes (fat cells) release numerous hormones and other factors that travel throughout the body signaling the musculoskeletal system, pancreas, liver, heart, adrenal glands, and central nervous system.1 Moreover, in people with excess body fat, adipo1266 f Physical Therapy

Adipokines
Adipokines, the molecules and hormones released by adipocytes, constitute a wondrous category of molecules that are only beginning to be understood and appreciated. At this time, more than 100 different adipokines have been shown to be released by fat cells; they include fatty
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Intricacies of Fat Table.

Major Molecules Released by Adipocytes or Adipose Tissue Macrophagesa
Adipokine(s) Leptin Hypothalamus Immune system Cardiovascular system Endocrine system Skeletal muscle Adiponectin Immune system Skeletal muscle Liver Site of Action Function Represses hunger, increases energy metabolism Keeps immune system up-regulated Anti-inammatory effect Regulates puberty and reproduction Improves insulin sensitivity Decreases release of inammatory molecules Increases fatty acid oxidation, glucose uptake, and lactate production Reduces levels of molecules involved in gluconeogenesis, increases free fatty acid metabolism Antiatherosclerotic effect Stimulates inammation Impairs vascular relaxation Transports vitamin A Impairs insulin signaling Impairs insulin signaling Binds to insulin receptors and mimics insulin Causes release of TNF- and interleukins (inammatory signals) Impairs insulin signaling Induces smooth muscle cell contraction and raises blood pressure Pro-inammatory effect Promotes insulin resistance Promotes insulin resistance

Cardiovascular system Resistin Immune system Cardiovascular system Retinol-binding protein 4 Plasma Skeletal muscle Tumor necrosis factor alpha (TNF-) Visfatin Skeletal muscle Skeletal muscle Immune system Interleukin 6 Angiotensinogen and angiotensin II Skeletal muscle Vascular system Adipose tissue Free fatty acids Skeletal muscle Liver
a

Adipocytes and other cells within fat tissue release molecules that work locally or are transported throughout the body.

acids, prostaglandins, steroids, and specic hormones that regulate hunger and metabolism.1 Some of these factors act within fat tissue in a paracrine fashion. Other factors travel through the bloodstream to distant sites as hormones with very specic effects. The following section reviews the major molecules released by fat cells (Table). Leptin The rst adipokine identied was a proteinleptinexpressed almost exclusively in fat cells12 (Fig. 1). Mice with mutations in the leptin gene or leptin receptors become extremely obese. Likewise, people with genetic leptin deciencies are
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severely obese and have impaired thermogenesis and insulin resistance; all of these conditions can be reversed if the person is treated with leptin replacement therapy.13 These ndings led to great enthusiasm for therapeutic leptin as a weight loss drug. Unfortunately, the administration of exogenous leptin to overweight and obese people lacking mutations in the leptin gene failed to result in weight loss because the body rapidly became resistant to leptin given as a drug.14 Within the body, leptin acts on the central nervous system to suppress appetite. Receptors for leptin are found in the hypothalamus and pro-

vide the normal satiation signal to the brain.15 Therefore, when excessive fat stores are available, leptin signals the brain to decrease appetite. Along with decreasing appetite, leptin increases energy consumption,16 making it a highly desirable hormone. In states of obesity, circulating leptin levels are high; therefore, one would assume that appetite would be low, but the brain does not respond normally to chronically high levels of leptin by decreasing appetite. Instead, the brain receptors appear to become resistant to high levels of leptin,17 just as overweight people became resistant when given leptin as a drug.14 Resistance and obesity appear to be signicant probPhysical Therapy f 1267

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Figure 1.
Single fat cells secrete different molecules depending on whether a person is of normal weight or obese. Healthy adipocytes from a person without obesity (illustrated on the left) would secrete low levels of leptin, visfatin, retinol-binding protein 4 (RBP4), and fatty acids. The cells might release small amounts of tumor necrosis factor alpha (TNF-) and resistin. Healthy cells would release large amounts of adiponectin (shown in red). Under states of obesity (illustrated on the right), the same adipocytes would be larger and would release only small amounts of adiponectin but would release high concentrations of leptin, visfatin, RBP4, and fatty acids (shown in red). Large amounts of resistin and TNF- would be released from the tissue, but they would likely originate from the macrophages in the fat, not the adipocytes themselves.

lems, as this same process explains why obese and sedentary people do not efciently utilize glucose in their skeletal muscles. The muscles become resistant to insulin. In addition to its role in regulating weight, leptin regulates puberty and reproduction, acting like other growth hormones. This role may explain why overweight adolescent girls with high leptin levels typically experience puberty at an earlier age than girls of normal weight. A study of adolescent boys found that abnormal leptin signaling indicates metabolic irregularities at early phases in the disease process, when other tests are still negative.18 Thus, a change in leptin levels has been suggested to be an early plasma marker for predicting metabolic syndrome, at least in adolescents. Receptors that bind leptin are also expressed throughout the cardio1268 f Physical Therapy

vascular and immune systems.19 Humans with a rare genetic mutation resulting in a lack of leptin have hyporesponsive T cells and other immune dysfunctions.13 Decreased leptin concentrations have been associated with immune diseases such as rheumatoid arthritis and intestinal inammation. Interestingly, a recent article linked leptin levels to damaged knee cartilage independent of body mass index (BMI); the authors suggested that the cartilage damage was hormonally related and that abnormal leptin signaling was one of the mediators.20 Adiponectin Adiponectin was rst identied by 4 different laboratories independently as an important circulating factor released from adipocytes.21 Adiponectin has several benecial effects. It has a strong anti-inammatory role and is protective against vascular diseases and metabolic diseases. It orig-

inates from subcutaneous fat; less is produced by intra-abdominal fat.22 Adiponectin is unique because, although most adipokines are released in higher quantities in states of obesity, adiponectin is released in lower levels in people who are obese compared with people of normal weight (Fig. 1). Adiponectin levels are reduced under conditions of insulin resistance, type 2 diabetes, and cardiovascular disease.23 Low levels of adiponectin predict the future development of both type 2 diabetes and cardiovascular disease.21,24 Low levels also predict weight gain in adolescents as the children move into adulthood.25 In general, adiponectin levels are higher in women than in men,26 and they appear to be associated with ethnicity. African-American and Filipino women have signicantly lower plasma adiponectin levels than white women, and those differences are inNovember 2008

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Intricacies of Fat dependent of body size or insulin resistance.27 Weight loss results in an increase in circulating adiponectin levels, which is accompanied by an improvement in insulin sensitivity in skeletal muscle.23 Adiponectin also is reported to have an antiatherosclerotic effect, as low levels of adiponectin are associated with coronary artery disease.28 At normal concentrations, it reduces the expression of vascular adhesion molecules involved in clot formation.29 It also reduces the activity of inammatory modulators released by macrophages, monocytes, and dendritic cells.30 Therefore, it is an important suppressor of inammation in the vasculature. Weight loss after gastric bypass surgery increases adiponectin levels.31,32 Interestingly, exercise training not accompanied by weight loss does not result in a change in adiponectin levels.33 Therefore, it appears that the most important parameter for determining adiponectin levels is fat, not tness. Weight loss, as well as tness, must be integral to designing an exercise protocol to return adipokine signaling to healthful levels in obese people. The therapeutic administration of adiponectin to reverse insulin resistance has been accomplished only in rodent models of diabetes. In animal models of both type 1 and type 2 diabetes, the injection of adiponectin resulted in signicant decreases in blood glucose levels.34 However, this result has not been successfully repeated in humans. Resistin Resistin was rst identied in 2001 as a protein secreted specically from adipocytes. It is called resistin because it induces insulin resistance in animals.35 Serum resistin levels are elevated under conditions of obesity, and the infusion of resistin produces
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insulin resistance.36,37 Recent studies in humans showed a consistent association between resistin and inammation,38,39 but a direct link between resistin and insulin resistance in humans is less clear. Although one study showed a link between increased resistin levels and insulin levels in women who were prediabetic,40 other researchers36 speculated that this link may occur through actions of leptin on the immune system that promote inammation. Resistin may have the direct effect of promoting insulin resistance only in rodents,16 and an association with insulin resistance in humans may act through inammatory steps. Also controversial is the site of production of resistin. Originally, it was assumed that adipocytes were secreting resistin, but recent evidence suggests that it may actually be produced by inammatory cells in fat41; this uncertainty is the reason why a question mark was included in Figure 1 for the origin of resistin. Much about resistin is yet to be determined, including whether it has any direct role in the pathology of type 2 diabetes in humans. Retinol-Binding Protein 4 Retinol-binding protein 4 (RBP4) was recently discovered during the examination of a mouse model with a genetic mutation that caused insulin resistance.42 Retinol-binding protein 4 is a circulating protein normally responsible for the transport of vitamin A (retinol). Plasma levels and the expression of this protein within adipose tissue are elevated in at least 5 different mouse models of insulin resistance and obesity.1 Increased RBP4 impairs insulin signaling in muscle, and the normalization of serum RBP4 levels leads to improved insulin action.43 In humans, plasma RBP4 concentrations are higher under conditions of impaired glucose tolerance and

type 2 diabetes.44 This increase is not associated directly with obesity as measured by either BMI41 or percentage of body fat.45 Therefore, although adipocytes produce RBP4, the increased levels associated with insulin resistance are independent of fat accumulation.46 In exercisetrained subjects with improved insulin resistance, a reduction in serum RBP4 concentrations has been measured.47 Tumor Necrosis Factor Alpha Tumor necrosis factor alpha (TNF-) is a small, secreted protein produced by many different types of cells with a variety of actions. The original reports of TNF- expression in obese rodents and humans appeared in the early and mid 1990s.7 In states of obesity, TNF- is produced in high levels, and insulin resistance ensues.48 Tumor necrosis factor alpha causes insulin resistance by inhibiting insulin receptor signaling and has an autocrine effect on adipose tissue itself. Recent evidence indicated that adipocytes produce and secrete TNF- but that the majority of the molecule associated with obesity is actually produced by macrophages that inltrate excessive fat.49 The macrophages release TNF- and other immune molecules, such as interleukins, under conditions of obesity (Fig. 2). Most of the TNF- that is released by fat cells is utilized locally and is not released into the circulation.50 Therefore, it has more of an autocrine or paracrine effect rather than a true endocrine effect (Fig. 2). In a very interesting study of 188 male subjects with risk factors for diabetes or cardiovascular disease, researchers looked for changes in several adipokines with exercise, changes in diet, or both.51 They found that only TNF- levels decreased with the interventions and that the decreases occurred when
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Intricacies of Fat

Figure 2.
Recruited macrophages enter fat under conditions of obesity. Under healthful (nonobese) conditions, adipocytes are small and have few resident macrophages (tan color), which are relatively inactive or release anti-inammatory molecules (left). Under conditions of obesity, new macrophages (blue) are recruited into the fat tissue and release large amounts of inammatory molecules (right). Those inammatory molecules may act at distant sites in the body or may activate the adipocytes in the fat, as shown for tumor necrosis factor alpha (TNF).

the subjects underwent exercise training or when they improved their dietary intake.51 Visfatin Visfatin is one of the most recently discovered adipokines and is so named because it is found at higher levels in visceral fat than in subcutaneous fat or other fat sites. Visfatin is released by adipocytes and binds to insulin receptors, stimulating glucose utilization in peripheral tissues; therefore, it mimics the effects of insulin.52 High levels of visfatin have been reported in humans with abdominal obesity.53 Visfatin is released by fat cells in response to TNF- and other inammatory markers.54 Hormones such as insulin, progesterone, and testosterone decrease the release of visfatin by adipocytes.55
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Visfatin is likely associated with diseases beyond diabetes. High levels of visfatin are detected in patients with inammatory bowel disease.16 Although visfatin is released by adipocytes in response to TNF-, it also induces the release of more TNF- and interleukin 6 and causes the proliferation of lymphocytes observations that researchers are still trying to interpret but that suggest that visfatin is closely linked to inammation. Other adipokines that are worthy of mention include angiotensin II, interleukins, and free fatty acids. The angiotensinogen signaling pathway is important in vascular control. Angiotensin II is one of the most potent vasoconstrictors produced by the body and is closely linked to high blood pressure. Interleukin 6 is cer-

tainly produced by adipocytes, as up to 30% of the total interleukin 6 in people who are obese may originate from their fat cells.56 Interleukin 6 may stimulate the movement of macrophages into adipose tissue in times of obesity and inammation. Free fatty acids released by adipokines originally were thought to be necessary as an energy source, and this is true. However, free fatty acids also can act as endocrine signals and are known to impair the actions of insulin.57 These are merely a few of the signaling molecules that are released by fat cells and that work locally or travel to distant sites in the body to exert their effects.

Exercise and Adipokines

Several studies have shown that aerobic exercise induces acute effects or long-term effects on adipokine
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Intricacies of Fat levels. In contrast, few, if any, studies have specically examined the effects of resistive exercises. In general, exercise that is associated with weight loss has the most inuence on adipokine levels. A 4-week aerobic exercise program for women resulted in a decrease in leptin levels starting after the rst week of the exercise protocol; this decrease was maintained throughout the exercise program.58 Surprisingly, leptin levels have been shown to change with exercise independent of weight loss. A group of teenage girls with type 1 diabetes and normal BMIs were placed in an exercise program. Although leptin levels increased in the nontrained control group, they remained constant for 6 months in the exercise group.59 In studies of the effects of exercise on adiponectin, the results have been mixed. Studies that have looked for changes in plasma adiponectin levels have often failed to measure any changes with exercise.60 In men who were lean and men who were overweight, exercise increased local adiponectin concentrations within adipose tissue but did not change plasma adiponectin levels.61 Exercise promotes the expression of more adiponectin receptors in skeletal muscle62,63; this nding is interesting because adiponectin decreases insulin resistance in skeletal muscle. Therefore, changes in adiponectin should be evaluated rst within fat and muscle tissues rather than in plasma. A 12-week aerobic exercise training program with weight reduction caused a signicant decrease in plasma visfatin levels in women without diabetes.64 Because visfatin mimics the action of insulin, it is viewed by some researchers53 as a positive adaptation to prevent further increases in glucose levels under conditions of obesity. One study examining changes in resistin levels with exercise showed no effects, even when leptin levels were reduced.65 Another study consisting of 16 weeks of exercise training showed signicant reductions in plasma resistin levels.66 Researchers will continue to sort out the nuances of the effects of exercise on adipocyte signaling; in general, however, exercise moves adipokine release to more normal levels in people who are obese. (Also see the related article by Turcotte and Fisher67 in this issue.) now understood that there is a great deal of cross talk between the insulin signaling pathway and the inammatory pathway in humans. Furthermore, one of the main molecules, if not the most important molecule, involved in that cross talk is TNF-. The exact mechanism leading from obesity to inammation is not clear, but there are several theories. One theory states that the larger number of enlarged adipocytes associated with obesity actually causes a local oxygen shortage, triggering a state of chronic hypoxia and local inammation in the surrounding cells.69 Conversely, it is known that adipocytes themselves can stimulate inammatory responses. Locally secreted adipokines such as resistin, leptin, and adiponectin attract proinammatory macrophages into adipose tissue, where they encircle dying adipocytes (Fig. 2). The macrophages release their own factors that further stimulate the inammatory process.70 In addition, obesity often is accompanied by increased levels of free fatty acids, which could activate proinammatory responses in blood vessels, fat cells, and immune cells.70 As explained earlier, macrophages inltrate adipose tissue at higher levels in states of obesity. The number of macrophages within fat tissue is directly correlated with the amount of fat tissue and the size of adipocytes. In states of obesity, 50% of the total cellular content in the fat may actually be inammatory macrophages, whereas in lean people, that percentage is closer to 10%.71 In states of obesity, new macrophages are recruited to adipose tissue (Fig. 2). These recruited macrophages behave in a manner very different from that of macrophages residing within adipose tissue in states of leanness.72,73 Resident macrophages have an antiinammatory role, whereas macroPhysical Therapy f 1271

Obesity Is a Chronic State of Inammation

Healthy adipocytes are inundated with vascular cells, neurons, and cells of the immune system. These cells are important in supporting healthy adipose tissue. However, in states of obesity, the immune cells become stimulated by adipokines and other factors to become overly active. Leptin alone is known to activate macrophages and helper T cells, increase the maturation and survival of thymic T cells, increase the release of interleukins, activate dendritic cells, and stimulate the proliferation of naive T cells.16 These actions stimulate a robust inammatory response within fat. The rst concept important to understand is that excess adipose tissue initiates several cellular pathways leading to chronic inammation. The link between chronic inammation and obesity was rst proposed in the 1960s, when epidemiology studies indicated that obese people had elevated levels of circulating inammatory markers. Since then, the results have been veried, and additional inammatory markers have been identied. It was not until 1993 that an important article, published in Science, demonstrated that adipocytes released TNF-, resulting in insulin resistance.68 At the time, TNF- was predominantly known to be an inammatory signaling molecule. It is

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Intricacies of Fat phages recruited to adipose tissue under conditions of obesity have a proinammatory role, perhaps because the 2 types of macrophages originate from different sources. Therefore, excessive fat cells lead to inammation. The next question is how the inammation in fat cells results in insulin resistance. De Luca and Olefsky74 proposed a 2-step progression in which the inammatory process is rst activated by macrophages within adipose tissue. Those signals spread in a paracrine fashion, activating inammation in nearby tissues and resulting in resistance to insulin signaling in those tissues. Free fatty acids are subsequently released from stimulated adipocytes, leading to secondary insulin resistance at distant sites, such as skeletal muscle.74 The actual process is yet to be elucidated. The body has endogenous antioxidant enzymes that limit free oxygen radical damage to cells. In the early stages of obesity, these enzymes become more active, ready to battle the obesity-related oxidative stress. With chronic obesity, antioxidant enzymes become depleted and can no longer maintain the balance.76 In cultured adipocytes, oxidative stress induces insulin resistance in individual fat cells, and exposure to antioxidants alleviates the resistance.77,78 Insulin resistance in adipocytes is an interesting observation, because it indicates that defects in the adipocytes of people who are chronically obese can no longer take up excess energy in the form of glucose for storage, ultimately leading to the hyperglycemia essential to type 2 diabetes. Although oxidative stress likely does not cause obesity, it certainly hastens the medical complications associated with obesity, including vascular diseases such as atherosclerosis and high blood pressure and metabolic disorders such as type 2 diabetes. It is important to be mindful of this information when prescribing exercise for people who are obese because they are more susceptible to oxidative stress during an acute bout of exercise than are people of normal weight.79 Vigorous exercise has been associated with more oxidative stress in people who are obese than has moderate exercise. Although this information is important, it should not discourage the prescription of exercise for people who are obese. The positive effects of long-term exercise are clear. Oxidative stress markers were reduced with 6 months of exercise even when a persons BMI did not change.80,81 In animal models, lipid peroxidation levels were lower in the skeletal muscle of endurancetrained rats than in that of sedentary control rats.82

All Fat Is Not Equal

Although there is a clear link between obesity and insulin resistance, diabetes, and cardiovascular disease, there are people with obesity who have no signs of these disorders. Up to 20% of people classied as obese, with a BMI of greater than 30, have a normal metabolic prole and normal insulin sensitivity.83 Other studies have shown that 20% of obese people also have normal cardiovascular proles, with no hypertension, normal lipid proles, and normal glucose tolerance.84 Humans show great variability in the distribution of fat. The heterogeneous nature of fat indicates that different types and locations of fat have different actions. Since the 1950s, it has been postulated that abdominal fat is a greater health risk than subcutaneous fat in other parts of the body, such as the thighs. In the 1980s, clear proof showed that fat on the thighs, typically seen in females, posed less risk for metabolic syndrome.85 In general, females have more body fat than males, and a greater percentage of it is stored in the lower body, with less visceral fat, than in even lean males.86 Research showed that when meals with low fat and high fat contents are compared, females more efciently take up the triglycerides from the high-fat meal in their lower-extremity adipose tissue than do males, who typically store the triglycerides in the abdominal region.87 Within the abdomen, there are subcompartments for fat, including subcutaneous, subfascial, and visceral (surrounding organs). Subcutaneous fat is rather benign, but visceral fat around the organs has been compared with a cancerous tumor, creating pathological conditions in nearby tissues (Fig. 3). A very important study published in 2005 measured visceral and subcutaneous abdominal fat and compared it with
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Stress of Obesity
It is clear that adipocytes have endocrine and immune functions. Beyond those roles, they are important in maintaining the level of oxidative stress in the body. Oxidative stress is caused by free oxygen radicals, which are superreactive oxygen molecules. In healthful states, low levels of free oxygen radicals are a necessary part of cellular respiration. They are balanced by antioxidants, including dietary products containing vitamins A, C, and E. In states of obesity, the balance is lost, and excess free oxygen radicals accumulate in tissues.75 Vincent et al75 demonstrated that obese people were far less likely to eat foods rich in antioxidants, such as fruits and vegetables, and suggested that people who are obese accrue an antioxidant deficit because of poor food choices. The introduction of low-fat diets, high in antioxidant activity, generally resulted in rapid decreases in oxidative stress biomarkers, even without weight loss.75

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Figure 3.
Fat distribution within the abdomen varies among people. A cross section of the abdomen shows organs that are relatively near each other in a lean person. With subcutaneous fat (under the skin), the arrangement of the organs is basically undisturbed, with a few adipocytes surrounding the organs (yellow circles). In the presence of large amounts of visceral fat, the organs may be shifted and further apart, with fat surrounding each one. People with normal body mass indexes can have visceral fat; only a computed tomography scan would reveal the visceral fat. However, most people with visceral fat also have excess subcutaneous fat, resulting in central obesity.

intramuscular and subcutaneous thigh fat.88 Using computed tomography (CT) scans of more than 3,000 people, the researchers found that visceral fat was the most important predictor of the development of metabolic syndrome, even in people of normal weight.88 Conversely, subcutaneous fat around the thighs was a negative predictor of metabolic syndrome.88 Even more telling are studies that monitored people after surgeries or procedures for weight loss. People who undergo liposuction, which is predominantly the removal of subcuNovember 2008

taneous fat, show no improvement in insulin sensitivity or other metabolic syndrome factors after the liposuction.89 In contrast, loss of visceral fat through conventional diets is associated with improved insulin sensitivity.90,91 Weight loss following gastric surgery is associated with decreased oxidative stress, improved blood lipid proles, and decreased levels of proinammatory markers.92 Therefore, fat surrounding the organs, especially the liver, may play a signicant role in the genesis of metabolic syndrome. Such observations support the notion that detrimental actions, including inammation, as-

sociated with adipocytes have dramatic effects on neighboring organs. When this information is applied clinically, it is obvious that waist circumference should be an important measurement taken for all people who are overweight or obese. Abdominal obesity is now recognized as a greater risk factor than overall obesity for a number of diseases, including type 2 diabetes and cardiovascular disease.93 It is more highly associated with high blood pressure than BMI measurements. Reproducible waist circumference measurements should be taken at the high
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Intricacies of Fat point of the iliac crest. However, a second important measurement is the maximum abdominal circumference. Ethnic and body type differences may cause changes in the distribution of abdominal fat, so that the maximum measurement is not always at the top of the iliac crest.93 fects of ectopic fat within specic tissues, such as the heart, pancreas, and liver, are highlighted here. However, Rasouli et al94 provided a detailed review of this topic. Lipid accumulation in liver cells (hepatocytes) may be among the most dangerous. It is a relatively common condition, termed hepatic steatosis (or fatty liver), and for years was not directly associated with obesity. Steatosis is a combination of adipocytes residing in the liver and excess lipid droplets within and around liver cells. Electron micrographs of the livers of diabetic rats showed expanded lipid droplets in those livers as well as a loss of healthy mitochondria with diabetes (Fig. 4). Liver steatosis is associated with hepatic insulin resistance and is common in metabolic syndrome. It is a predictor of type 2 diabetes and causes elevated levels of liver enzymes.99 Likewise, lipids can accumulate in pancreatic islet cells, the insulinproducing cells of the body. Excessive lipid droplets there result in cell dysfunction and even cell death in rodents.100 Research with diabetic rodents showed an increase in the number of lipid droplets in cardiac myocytes that was not reversed by endurance exercise training.101 Using a rat model of type 2 diabetes, other researchers102 showed that lipid accumulation in the heart was associated with necrosis of cardiomyocytes and contributed to the functional cardiomyopathy documented by Loganathan et al.103 For physical therapists, lipid deposits in skeletal muscle are innitely important. It has been known for a long time that skeletal muscle health is directly associated with type 2 diabetes. Seventy-ve percent of all glucose ingested is utilized, via insulin, by skeletal muscle,104 which is why sedentary people are at such a high risk for obesity and diabetes. When insulin does not act normally to move glucose into skeletal muscle, because of aberrations in either insulin receptors or downstream signaling molecules, insulin resistance ensues. Diabetes has been shown to be associated with excess lipid droplets in the skeletal muscle cells of rats with diabetes.105 People with insulin resistance frequently have extra lipid droplets, known as intramyocellular lipids, in their skeletal muscle.104 In fact, the level of lipid accumulation in skeletal muscle is highly correlated with the amount of insulin resistance present.106 This relationship is independent of obesity as measured by waist-to-hip ratio, percentage of body fat, or BMI.107 Women oxidize more lipids during endurance exercise than men, and this higher degree of fat oxidation is associated with the presence of more lipid droplets in skeletal muscle.108 Intramyocellular lipid levels in muscle have been reported to decrease with weight loss, resulting in less insulin resistance.109 The treatment of people with type 2 diabetes with insulin-sensitizing drugs such as metformin reduces the levels of lipid accumulation in both the liver and skeletal muscle.110 Likewise, people with high levels of circulating adiponectin, which is protective against insulin resistance, have less ectopic fat accumulation in muscle and other tissues.111 It appears that weight loss and exercise would benet skeletal muscle function and decrease the incidence of type 2 diabetes by reducing the accumulation of ectopic fat in muscle. A confusing observation is the fact that well-trained endurance athletes also have high levels of lipid deposits in their skeletal muscle, just like people who are sedentary and obese. Therefore, endurance athletes and people who are sedentary and obese
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Fat in Nonfat Cells

Another subtlety in contemplating fat is its accumulation in the form of lipid droplets in cells that are not adipocytes. Lipid droplets found in nonfat cells are referred to as ectopic fat94 and are a normal component of all cells. They provide an immediate source of energy for cells. In obesity, the ability of adipose tissue to store excess calories is impaired because adipocytes themselves become insulin resistant; therefore, they cannot take up glucose.95 Consequently, ectopic fat accumulates in the organs and in skeletal muscle.96 The abnormal lipid droplets can cause lipotoxicity and programmed cell death and have been termed weapons of lean body mass destruction.97 Therefore, in states of obesity, not only do adipocytes (fat body mass) increase in size and number but also the lipotoxicity of nonadipocytes causes a decrease in lean body mass through lipotoxicityinduced cell death. In a study of the offspring of people with type 2 diabetes, boys with normal glucose tolerance were found to have less ectopic lipid accumulation and less visceral fat than boys with increased insulin resistance.96 Ectopic fat in skeletal muscle is a strong predictor of type 2 diabetes.98 Only recently have researchers begun to recognize that adipokines (adiponectin, leptin, RBP-4, and others) can be produced by nonfat cells when ectopic fat is present, especially in skeletal muscle and the liver.46 These adipokines released within nonfat tissues can have dramatic physiological results. The ef1274 f Physical Therapy

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Intricacies of Fat

Control LD

ER

Diabetic EM EM LD

Nuc
Figure 4.
Ectopic lipid droplets in livers of diabetic and control rats. Electron micrographs illustrate lipid accumulation and loss of healthy mitochondria in livers of diabetic rats relative to matched control rats. The lipid droplet (LD) in the liver of a diabetic rat is larger than the lipid droplet in the liver of a nondiabetic rat. The droplet identied in the control liver is located in a healthy cell with abundant, well-formed mitochondria (arrows), whereas the lipid identied in the diabetic liver is located in a dying cell with expanded mitochondria (EM). Other cellular components shown include the nucleus (Nuc) and the endoplasmic reticulum (ER).

both have elevated levels of intramyocellular triglycerides, but the rst group is very insulin sensitive, whereas the second group is insulin resistant.97 Theories abound, but one that seems more plausible is that, with exercise training, skeletal muscles need more energy and therefore lipid droplets are more abundant in muscle cells as a quick source of energy. Metabolism of fatty acids
November 2008

from muscle is extremely sensitive to physical activity.112 In an athlete, there would be a continual turnover of those muscle cell lipid droplets, whereas in a person who is sedentary and obese, the lipid droplets would be incorporated into the muscle cells and would remain there. It could be the long-term storage of those lipid droplets that makes them sensitive to peroxida-

tion, subsequently releasing damaging by-products, including TNF- and the inammatory molecules discussed earlier.113 Regardless of the mechanism, the conclusions are difcult to overlook. Exercise is pivotal to ghting diabetes and a variety of other obesity-related diseases. Skeletal muscle utilization of glucose during exercise keeps average plasma glucose levels in
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Intricacies of Fat check, decreases the risk for insulin resistance, and decreases ectopic fat accumulation. (Also see related articles in this issue by Hilton et al114 and Marcus et al115 about the inltration of fat into the muscle of people with diabetes mellitus.)
The author wishes to acknowledge Dr Yvonne Searls for generously donating the liver electron micrographs. This article was submitted January 28, 2008, and was accepted April 16, 2008. DOI: 10.2522/ptj.20080034 14 Zelissen PM, Stenlof K, Lean ME, et al. Effect of three treatment schedules of recombinant methionyl human leptin on body weight in obese adults: a randomized placebo-controlled trial. Diabetes Obes Metab. 2005;7:755761. 15 Pelleymounter MA, Cullen MJ, Baker MG, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269:540 543. 16 Lago F, Dieguez C, Gomez-Reino J, Gualillo O. Adipokines as emerging mediators of immune response and inammation. Nat Clin Pract Rheum. 2007; 3:716 724. 17 Yamada T, Katagiri H. Avenues of communication between the brain and tissues/organs involved in energy homeostasis. Endo J. 2007;54:497505. 18 Nakatani H, Hirose H, Yamamoto Y, et al. Signicance of leptin and high-molecular weight adiponectin in the general population of Japanese male adolescents. Metabolism. 2008;57:157162. 19 Kougias P, Chai H, Lin PH, et al. Effects of adipocyte-derived cytokines on endothelial functions: implication of vascular disease. J Surg Res. 2005;126:121129. 20 Ding C, Parameswaran V, Cicuttini F, et al. Association between leptin, body composition, sex and knee cartilage morphology in older adults: the Tasmanian Older Adult Cohort (TASOAC) study. Ann Rheum Dis. 2008 Jan 3 [Epub ahead of print]. 21 Oh DK, Ciaraldi T, Henry RR. Adiponectin in health and disease. Diabetes Obes Metab. 2007;9:282289. 22 Fain JM, Madan AK, Hiler MI, et al. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology. 2004; 145:22732282. 23 Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol. 2004;24:29 33. 24 Spranger J, Kroke A, Mohlig M, et al. Adiponectin and protection against type 2 diabetes mellitus. Lancet. 2003;361: 226 228. 25 Saltevo J, Vanhala M, Kautiainen H, Laakso M. Levels of adiponectin, C-reactive protein and interleukin-1 receptor antagonist are associated with the relative change in body mass index between childhood and adulthood. Diab Vasc Dis Res. 2007;4:328 331. 26 Cnop M, Hael PJ, Utzschneider KM, et al. Relationship of adiponectin to body fat distribution, insulin sensitivity, and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia. 2003;46:459 469. 27 Araneta MR, Barrett-Conner E. Adiponectin and ghrelin levels and body size in normoglycemic Filipino, AfricanAmerican, and white women. Obesity (Silver Spring). 2007;15:2454 2462.

References

Conclusion
Concepts concerning the role of fat in health and disease are changing nearly every week. New observations, theories, and empirical data have forced endocrinologists, scientists, immunologists, and the general public to change their long-held beliefs about fat. Without question, researchers are only at the beginning of a long scientic journey to an understanding of the links between fat and diabetes, cardiovascular dysfunction, cancer, and a myriad of other diseases. Some key points to consider are as follows: (1) fat has both endocrine and immune functions as well as an energy storage function; (2) adipokines released by fat cells are benecial in health unless the body accumulates too much fat (especially visceral), resulting in abnormal signaling that can actually increase the progression of disease; (3) chronic inammation is present within excess fat tissue and is involved in the progression to insulin resistance and diabetes; and (4) the anatomical and cellular locations of fat play a role in how fat affects health. This intriguing story will continue to unfold as the negative consequences of obesity overwhelm the health care system. Understanding the mechanisms involved will help researchers and clinicians design interventions that can lessen the impact. However, the most important interventions will be behavioral changes, including less sedentary behavior, a task well suited for physical therapists.
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Intricacies of Fat Lisa Stehno-Bittel PHYS THER. 2008; 88:1265-1278. Originally published online September 18, 2008 doi: 10.2522/ptj.20080034

References

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