Obesity 0025-7125/89 $0.00 + .

20

Health Risks of Obesity

Ahmed H. Kissebah, MD, PhD,* David S. Freedman, PhD,t

and Alan N. Peiris, MD, FACP:j:

Numerous studies have shown that overweight people are at increased risk for
several diseases. A 12-year follow-up of 336,000 men and 419,000 women by the
American Cancer Society, for example,106 shows that persons who are greater than
40 per cent overweight suffer increased mortality from diabetes, coronary heart
disease, and cancer. The importance of less severe obesity, however, has remained
controversial, with several studies reporting that moderate obesity is not associated
with increased mortality.5. 64. 82 This article critically reviews the body of evidence
implicating obesity as a risk-factor disease and possible reasons for the many
conflicting findings. A classification of obesity based upon the site of body fat
distribution and the possible biologic mechanisms associating regional adiposity with
morbidity are addressed.

RELATION OF OBESITY TO HEALTH

The prevalence of obesity in the United States is increasing: Approximately 34

million adults are considered to be overweight (85th percentile for weight/height2 ),
with about 12 million severely overweight (95th percentile). Based on body mass
index (BMI, kg per m2) data from the National Center for Health Statistics, severe
overweight corresponds to a relative weight of equal to or greater than 145 per cent
of ideal for men of medium frame. lOO
In most population-based research, relative weight, weight/height2 , or skinfold
thicknesses have been used as surrogates for obesity. Although skinfold thicknesses
generally show the highest correlation with direct measures of adipose tissue, a

From the Divisions of Endocrinology and Metabolism, and Biostatistics and Clinical Epide-
miology, Medical College of Wisconsin, Milwaukee, Wisconsin

*Professor of Medicine; and Program Director, Clinical Research Center, Froedtert Memorial
Lutheran Hospital
tAssistant Professor of Biostatistics and Clinical Epidemiology
tAssistant Professor of Medicine; and Attending PhYSician, Froedtert Memorial Lutheran
Hospital

Supported in part by grants Nos. HL34989 and RR00058 from the National Institutes of
Health

Medical Clinics of North America-Vo!. 73, No. 1, January 1989 111

112 All:\1ED H. KISSEBAH ET AL.

Table 1. Mortality Rates* for Selected Diseases from

the American Cancer Society Prospective Studyt
(PER CEI\T)

DISEASE SEX <80 80-89 90-109 110-119 120-129 130-139 2-140

Total deaths M 1.25 1.05 1.0 1.15 1.27 1.46 1.87
F 1.19 0.96 1.0 1.17 1.29 1.46 1.87
Diabetes M 0,88 0.84 1.0 1.65 2.56 3.51 5,19
F 0.65 0.61 1.0 1.92 3.34 3.78 7,90
Coronary heart M 0.88 0.90 1.0 1.23 1.32 1.55 1.95
disease F 1.01 0.89 1.0 1.23 1.39 1.54 2.07
All cancers M 1.33 1.13 1.0 1.02 1.09 1.14 1.33
F 0.96 0.92 1.0 1.10 1.19 1.23 1.5.5
Colorectal M 0.90 0.86 1.0 1.26 1.23 1.53 1.73
F 0.93 0.84 1.0 0.96 1.10 1.30 1.22
Endometrial F 0.89 1.04 1.0 1.36 1.85 2.30 .5.42
Breast F 0.82 0.86 1.0 1.19 1.16 1.22 1.53
Prostate M 1.02 0.92 1.0 0.90 1.37 1.33 1.29
*Mortality ratio is the age-adjusted and sex-specific mortality rate in each weight category
divided by the rate for persons in the 90-109 percent category.
tData from Lew EA, Garfinkel L: Variation in mortality by weight among 750,000 men
and women. J Chronic Dis 32:563, 1979.

high degree of site and observer variability exists in their measurements. Because
height and weight measurements are obtained easily and are reproducible, various
height-for-weight indices typically have been related to disease. Body mass index
generally shows the largest correlation with other measures of adiposity, and is
weakly correlated with height. Body mass index therefore often is considered to be
the "best" weight-for-height index. &4 Although there are conflicting opinions,,04 the
various weight-for-height indices are highly intercorrelated and order persons almost
identically.
Diabetes Mellitus
Obesity is the most powelful risk factor for noninsulin-dependent diabetes
mellitus (NIDDM), with both its magnitude and duration being important consid-
erations. H" Ecologic studies show a strong correlation between relative weight and
the prevalence of diabetes across populations,16fi and cross-sectional studies show
that diabetic patients have an increased relative weight. 140 Prospective studies in
the United States,92, 106 Sweden, 100 Israel, H5 and Norway 167 also show that overweight
increases the risk of diabetes. A 12-year study, for example, 106 showed that, compared
with persons of "ideal" weight, those with relative weights equal to or greater than
140 per cent have mortality ratios of 5. 2 (men) and 7.9 (women) because of diabetes
(Table 1). These mortality ratios are greater than for any other disease.
Although negative findings have been reported, they likely are attributable to
weight loss among diagnosed diabetics, obesity of short duration, or the nonrepre-
sentativeness of undiagnosed diabetics. l65 Knowler and coworkers,92 for example,
have shown that BMI is related more strongly to the incidence, rather than the
prevalence, of NIDDy[ among Pima Indians.
Cardiovascular Disease
Data collected by insurance companies first showed overweight to be associated
with increased morbidity and mortality from heart disease, with overweight men
having a 49 per cent higher death rate from cardiovascular disease than men of
"optimal" weight. 111 These insurance studies have been criticized on methodologic
HEALTH RISKS OF OBESITY 113

grounds, 15, 82 however: (1) obese persons were greatly under-represented among
policyholders, with those enrolled likely having a high prevalence of undisclosed
diabetes and hypertension, and (2) both the anthropometric and follow-up data
often were of poor quality . .\1ore recently, the American Cancer Society studi 06
showed a linear relation between self-reported relative weight and subsequent
coronary heart disease death in volunteers (see Table 1).
Numerous cross-sectional studies have found obesity to be related to adverse
levels of several cardiovascular disease (CVD) risk factors, including blood pressures,
lipids, and glucose. Several prospective studies also indicate that the increased
CVD risk in overweight persons primarily is related to an adverse risk-factor
profile. 22, 135 Recent results,73 however, suggest that additional factors, in part, are
responsible.
Although extremely obese persons (BMI greater than 30 kg per m 2) are at high
risk for CVD,82 the relation of moderate obesity to CVD remains controversial.
Geographic studies" indicate that differences in CVD rates among countries is not
attributable to differences in relative weight or skinfold thicknesses. Analyses of
secular trends do not support an association between overweight and CVD: The
proportion of overweight adults in the United States has increased over the past
two decades, 160 but CVD mortality has shown a concomitant decrease. Furthermore,
no consistent relation of weight, weight/height", or subcutaneous fat to coronary
atherosclerosis has been observed in autopsy studies,116 and weight gain is not
associated with the progression of atherosclerosis in arteriographically examined
individuals. 94
Prospective studies also have yielded conflicting results. In a review of 13
studies, Keys82 concluded that only one showed a definite association between
overweight and coronary heart disease. Reviews by Larrson and associates, 100
Hubert,72 and Barrett-Connor lO also illustrate substantially different results among
the prospective studies, with the relation of moderate obesity to CVD considered
to be small or nonexistent 5 , 82, 112 to "consistent and substantial. "159 Interestingly, a
U -shaped relationship between relative weight and CVD has been observed in
several studies,74, 82, 134, 161, 167 often with a minimum at 15 to 25 per cent overweight.
Differences in statistical methods cannot account for these disparate findings:
Each of eight populations included in the Pooling Projece 34 shows a different
relationship of relative weight-to-CVD incidence, even though similar analyses were
used in each cohort. Results from the separate studies included: (1) no association,
(2) a U-shaped pattern, (3) a threshold effect, and (4) a stepwise association. 10
Endocrine Disorders
It has long been recognized that obesity is associated with impotence and
oligospermia in men, and with amenorrhea and decreased fertility in women. 143
Subsequently, other disorders in women, including early menarche, 51 delayed
menopause,148 and anovulatory cycles 66 148 have been associated with obesity.
Obese postmenopausal women show an increased conversion of androstenedi-
one to estrone. Among these women, adipose tissue serves as the major source of
estrogen formation, with the conversion of androstenedione increasing from 1 to 2
per cent in normal weight subjects to 12 to 15 per cent in women who weigh over
300 lb. 149 This extraovarian estrogen (which is physiologically active) in conjunction
with observations that exogenous estrogens increase the risk of cancer,33 in part,
may explain the increased cancer incidence in obese females. 71 Estrogens likely act
as promoters, maintaining the growth of the tumor after neoplastic changes have
occurred.
The production of androstenedione is increased in obese women'6 and, although
conflicting findings have been reported, levels of sex hormone binding globulin are
decreased. 29 Obesity also is known to influence the production and/or circulating
114 A!l\IED H. KISSEBAH ET AL.

levels of androstenedione, DHEA, androgens, cortisol, growth hormones, and

prolactin. w,
Cancer
By 1940, both animal and human studies had indicated that obesity and
overnutrition were related to cancer,I56 and subsequent insurance studies ll :l agreed
with these early findings. Most studies of obesity and cancer have not been based
on representative longitudinal data, however, and the numerous case-control studies
have been subject to considerable bias. Albanes 2 recently has reviewed many of the
studies on overweight and cancer.
Although based on self-reported height and weight data, the American Cancer
Society study](lfi showed increased mortality caused by cancer among overweight
persons (see Table 1). Compared with persons of average weight, men who were
40 per cent or more overweight had a mortality ratio of 1.33 for all cancers; the
comparable value among overweight women was 1.55. Whereas the association
between overweight and cancer in women was linear, however, thin men (relative
weight less than 80 per cent) showed an increase in cancer mortality, likely
attributable to confounding by cigarette smoking. The cancer sites most strongly
related to overweight in men were colon/rectum and prostate, and in women,
endometrium, gallbladder, cervix, ovary, and breast. These account for one half of
all cancers in women.
Endometrial Cancer. The high prevalence of overweight women among patients
with endometrial cancer has long been recognized," and there now is persuasive
evidence that endometrial cancer is associated with increased body weight. Cancer
of the endometrium was the site most strongly associated with obesity in the
American Cancer Society prospective study (see Table 1), with women who were
over 40 per cent overweight showing more than a four-fold increase in mortality.
Case-control studies consistently have demonstrated an association between
overweight and endometrial cancer, 26. 54. 70. 80. 102. 171 with the risk of endometrial
cancer increasing up to 20-fold among the most overweight. 70. 102 Furthermore,
unlike breast cancer (see next section), overweight appears to be related to
endometrial cancer even in premenopausal women. 70 . 102 An increased risk of
endometrial cancer also has been related to overweight during adolescence" and
early adulthood. '"
Breast Cancer. Although the bimodal age distribution of breast cancer incidence
is well known, the American Cancer Society study found the relation between
overweight and breast cancer mortality to be linear, with mortality ratios ranging
from 0.82 in women who were less than 80 per cent of average weight to 1.53 in
women greatcr than 40 per cent above average weight (see Table 1). Based on the
aggregation of obesity, hypertension, and hyperglycemia in post- (but not pre-)
menopausal breast cancer patients, however, de Waard and colleagues·"l4 hypothe-
sized that pre- and postmenopausal breast cancer essentially are two different
diseases. Subsequent studies generally have supported this distinction. Weight and
body size have been related to breast cancer incidence in several epidemiologic
studies 26 . 151 after stratification by menopausal status, but the association with body
size is found consistently only for postmenopausal women. 32, 69,108 Although a negative
association between overweight and breast cancer risk among premenopausal women
has been reported,69, 124, 168 this may be the result of easier detection,w'
The importance of overweight in the etiology of breast cancer was emphasized
by de Waard,15 who suggested that approximately half of the difference in breast
cancer incidence between the Netherlands and Japan may be caused by differences
in body weight and height. Even small increases in overweight are likely related to
breast cancer incidence,106 and increased body weight is associated with a high
recurrence of breast cancer following mastectomy. 117 There may be a lag time in
HEALTH RISKS OF OBESITY 115

the relation of overweight to breast cancer however: The effects of overweight

among postmenopausal women may be rcstrictcd to those 50 ycars of age or older. 10'
As previously discussed, the increase in incidcnce of brcast cancer following
menopause may rcflect the continuing production of cstrogens in adipose tissue
without antagonism by progesterone. The specific mechanism for the increased
levels of free estrogen remains controversial, 144 however, and it has been suggcsted
that height may be as important as weight in determining brcast cancer risk. 31.133 If
the mechanism for thc increascd breast cancer risk among obese women is the
extraovarian production of estrogen, then the absolute adipocytc mass (rather than
the amount of fat relative to height) may be the crucial factor. Negative results
conccrning the relationship of breast cancer to height also have been rcported.107
Prostate Cancer. Geographic corrclations between prostate cancer and femalc
breast cancer suggest a common etiologic background. m Results of the American
Cancer Society study lO6 indicatc a 20 to 30 per cent increase in prostate cancer
mortality in men who are 20 per cent or more overweight (see Table 1). A strong
association between overweight and prostate cancer also was secn in a recent
prospcctive studyl": Men whose relativc weight was 130 per cent or more of
average were 2.5 times as likely to die from prostate cancer during a 20-year follow-
up period than were men of average weight.
However, a case-control study yielded negative results J72 and no effect of height
or various somatotypes on subsequent prostate cancer was found in a retrospective
cohort study.5& Although estrogen receptors havc been found in ncoplastic prostatic
tissue,119 the possible mechanism for the obesity-associated incrcase in prostatc
cancer remains uncertain. It also is possible that overweight is related to the
detcction of prostate cancer rather than to its incidence.
Colon Cancer. Persons who werc 40 per cent or more overweight in thc
American Cancer Society Studyl06 showed an increased mortality (73 per cent men,
22 per cent women) from colorcctal cancer (see Table 1). A recent prospective study
of 8000 middle-aged Japanese men also indicatcd that BMI at age 25 and adult
weight gain each are associatcd with an incrcascd risk of colon cancer in older
men. 120 Another prospective study of Sevcnth-Day Adventists found that males who
were 125 per cent or morc overwcight showed more than a three-fold incrcase in
mortality causcd by colon cancer over a 21-year period. l3.3 Case-control studics have
yielded conflicting results, however, with both positive173 and negative"IJ findings
reported.

POSSIBLE EXPLANATIONS FOR INCONSISTENT FINDINGS

Although it is possible that a primary factor causes both obesity and other
disease, there are scveral explanations that possibly could reconcile the contrasting
findings concern cd with an etiologic relationship between obesity and these other
diseases.
The size of the sample was not large enough to detect the hazards of moderate
obesity. It has been observed 160 that, of the frequently cited studies reporting no
association between obesity and mortality, only three followed more than 4000
subjects and, of these, two failed to exclude subjects with health problems at
baseline. However, KeysR2 has emphasized the distinction between a statistically
significant association between overweight and mortality (which can be achieved
with very small differences in large studies) and the clinical importance of these
findings.
Moreover, the lack of an association between obesity and mortality is not
limited to small studies. In a Norwegian study of 1.8 million people, 161 overall
mortality was related inversely to baseline BMI even after excluding deaths within
116 AII~IED H. KISSEB.A.I1 ET AL.

the first 5 years of follow-up. Furthermore, a e -shaped relation was seen in a study
of 18,000 men after deaths that occurred in the first 2 years of follow-up were
excluded. "
The distribution of other risk factors, particularly cigarette smoking, may
differ between ohese and nonohese persons. In the Framingham study, more than
80 per cent of men who were underweight were smokers whereas only 55 per cent
of men whose relative weights were 140 per cent or higher reported smoking, and
it was shown that the effect of underweight on CVD risk was almost entirely due
to smoking. 53 The possible confounding effects of high socioeconomic status also
may explain the negative results of some case-control studies examining obesity and
breast cancer. 144
Barrett-Connor,lo however, has suggested that smoking is unlikely to explain
all the conflicting results concerning obesity and CVD. For example, no consistent
association was seen between overweight and CVD mortality in nonsmoking men
followed for 10 years. l' Although it is possible that cigarette smoking also may
account for the increased incidence of lung, stomach, and bladder cancers that have
been observed in underweight persons, Nomura and colleagues 120 found that, even
after controlling for cigarette smoking, increases in weight remained inversely
associated with these cancers.
Obesity may exert its deleterious effects only after a long follow-up period.
Harrison~' has emphasized that all prospective studies with 15 or more years of
follow-up have shown an association between high relative weight and mortality.
The effect of the length of follow-up on CVD risk has been documented particularly
well in two prospective studies: :vIanitoba and Framingham. In each study,
associations between body mass indices and CVD became apparent only after 16 135
or 8 to 1447 73 years of follow-up. West lfi5 also has stressed the importance of the
duration of obesity in diabetes.
But, although a long follow-up would result in more events and, therefore,
more statistical power, the long-term importance of overweight still has been
questioned. In a 30-year follow-up of 284 men, for example, the mean BMI of those
dying from coronary heart disease was only 3 per cent greater than those who
remained alive. '2
Low-weight persons are thin because they already have the disease in question.
Results of the Whitehall Study'· show the effect of not excluding persons with
cancer: A strong inverse relation between baseline BMI and total cancer mortality
was observed during the first 2 years of follow-up. This "force of mortality," which
should be greatest in studies with short follow-up, also may explain the inverse
relationship of baseline BMI to stomach and lung cancer incidence,'20 and why all-
cause mortality in the second 12 years in Framingham showed a stronger association
with relative weight than in the first 12 years. 79
Although this effect also should exist in studies that have used self~reports
(rather than physical examinations) to exclude baseline cases, at least some have
found a linear, stepwise relation of overweight to both CVD lO6 and cancer. IOu. 151 In
addition, although the effects of (sub)clinical disease would weaken with longer
periods of study, a low B:vII has remained associated with increased mortality after
274 or 5 161 years of follow-up. The U -shaped association seen in some studies
therefore is unlikely to be caused entirely by the inclusion of diseased persons.
The relationship of obesity to CVD and cancer may differ according to the
end-point studied. Although 24-year follow-up data from the Framingham study2'
indicate that increased relative weight is related to sudden death, angina pectoris,
and myocardial infarction, the latter association is weaker and was not apparent
after 12 years of follow-up. Differences in the relationship of overweight to cancers
at various body sites also may dilute its association with overall cancer incidence
(or mortality). Among men in the American Cancer Society study, relative weight
HEALTH RISKS OF OBESITY 117

was related negatively to cancers of the lung and urinary bladder, and B.\11 has
been shown to be associated inversely with both lung and stomach cancer incidence
in another prospective study. 120 Furthermore, the classification of cancers according
to morphology (rather than sitc) may reveal unsuspectcd associations, and it is
possible that the relationship of overweight to the incidencc of cancer (or CVD)
differs from its relationship to mortality.
Although these findings suggest that the relationship of overweight to a specific
manifestation of CVD or cancer at a specific site may be hidden by thc inappropriate
grouping of cases, they also may be a result of chance fluctuations, given the small
numbers involved. In contrast to the Framingham findings,28 other prospective data
indicate that, compared with angina pectoris, overweight is related more strongly
to myocardial infarction. 22
The crude methods used to define obesity in most epidemiologic and clinical
studies have little relation to adiposity. A possible misclassification of obese persons
could result in only the extremely obese (or extremely thin) classified correctly,
which could explain the lack of association between modest overweight and disease.
Body mass index is correlated highly with skinfold thicknesses and body density
but it fails to "explain" one-third to one-half of the variability in these more accurate
measures,82 and does not distinguish between adiposity, muscularity, and edema.
In addition, the association between B.\11 and obesity may not be the same for all
ages B": Excess weight results from muscularity most often in young male subjects.
The possibility of misclassifying obese persons has been demonstrated in several
studies. After adjusting for relative weight, for example, diabetic subjects have less
muscle mass than do nondiabetics l "7 and, independently of relative weight, skinfold
thicknesses are predictive of subsequent diabetes."2 Compared with relative weight,
baseline measurements of skinfolds are more predictive of subsequent CVD.
Furthermore, the possibility that the various weight/height indices may not be
interchangeable lO4 has been suggested as an explanation for the inconsistent reports
between obesity and breast cancer. 170
More direct measures of body fat do not improve the prediction of CVD,
however. Among 1483 consecutive referrals, the use of tritium dilution showed only
a small difference in body fat between patients with and without coronary disease. Hi:l
Although these results used prevalence (rather than incidence) data, Larrson and
coworkers lOo found no association between obesity (as assessed by total body
potassium) and the incidence of angina or myocardial infarction over a 10 to 12.5
year follow-up period.
The association between obesity and various complications may differ among
various age groups, with the favorable health margin associated with leanness
diminishing among older persons. Insurance data and results from several prospec-
tive studies indicate that the relationship of overweight to both total mortality" lOB, III
and CVD incidence 22. 47 • 104, 135 is strongest in young (that is, less than 50 or less than
40 years of age) persons. Similar findings also have been reported in a clinical study
of 200 morbidly obese men, initially between the ages of 23 and 70 years."
Compared with the expected mortality, after 7.5 years, the 25- to 34-year-olds
showed a 12-fold increase, but men who were 65 years or older showed only a two-
fold excess.
This decreasing effect of overweight may be caused by the increased mortality
of overweight persons at younger ages, resulting in the selective survival of
"resistant" persons at older ages. Alternatively, obesity may be a risk factor only
for premature CVD, or weights at older ages may be less typical of a person's
lifetime exposure to obesity.
Weight increases during adulthood may be more important than the actual
degree of overweight. Many events in prospective studies occur long after the
baseline examination, but relatively few studies have examined the importance of
118 AH~IED H. KISSEBAH ET AL

weight changes during follow-up. Evcn after adjusting for relative weight in early
adulthood, however, subsequent changes in weight were related significantly to the
26-hour incidence of CVD7J and to the incidence of angina pectoris in women. 121
Weight gain during adulthood also has been related to adverse changes in several
CVD risk factors 6 . 121 and may increase the risk of breast 108 124 and endometriaP71
cancer.
The timing of obesity also may be important. Abraham's team ' found that the
prevalence of cardiovascular renal disease and hypertension in middle-aged, over-
weight adults was greatest in those who were thin as children. Furthermore, Albrink
and Meigs 3 found that moderate obesity attained after maturity was related more
strongly to hypertriglyeeridemia than was lifelong obesity; they also noted that
"acquired" obesity in males tended to be localized in the trunk.
Obesity may be a surrogate risk factor, reflecting physical inactidty,'" 122
dietary intake,85. 144. 169. 170 or the effects of other body components. Tannenbaum 156
suggested that factors controlling weight may be more important in the etiology of
cancer than the resultant increases in weight. It is possible that the relationship of
obesity to CVD also is indirect: The observation that obesity in Africa is not
associated with increased mortality has been attributed to dietary differences. 162 The
results of several recent studies, however, suggest that the relationship of diet to
cancer l33. 151 and CVD 85 exists independently of obesity.
Obese persons usually have an increased lean body mass, and it has been
suggested that the amount of muscle,'52 rather than adipose tissue, shows the
strongest association with CVD. Results indicate that blood pressure may be
correlated more strongly with body build l41 than with adipose tissue and, after
accounting for lean body mass, fat mass shows no residual association with blood
pressure. H\4 In addition, although the prevalence of hypertension and hypercholes-
terolemia is greatest in adults who arc overweight (based on kg per m 2) and obese
(based on the sum of skinfold thicknesses), these complications frequently arc seen
among adults who are overweight but not obese. 160 These observations may reflect
an association between body build (frame size and muscularity) and the pattern of
body fat distribution (see next section).
It is possible that a moderate excess of body fat may confer some protective
advantages. The obese may have different dietary patterns, stress adaptation, or
differences in protective endogenous hormone levels. But, although there is
disagreement between studies, overweight persons do not necessarily consume
more alcohoF5 or fiber. [3 Obese men may have higher levels of endogenous estrogen
than do lean men, but endogenous estrogen levels are not elevated in male survivors
of myocardial infarction compared with controls.2.3

OBESITY AS A HETEROGENEOUS DISORDER:

ROLE OF BODY FAT DISTRIBUTION

Systematic methods to categorize human body shape were introduced in the

1930s by Sheldon,'47 with the use of three primary components to describe body
shape: endomorphy (roundness), mesomorphy (muscle, bone, and connective tis-
sue), and ectomorphy (linearity and fragility). (These characteristics later were
shown to be predictive of certain manifestations of CVD. 27152) Skerlj and coworkers J51l
subsequently proposed that, in addition to generalized obesity, adipose tissue could
be characterized by "vectors" describing the localization of body fat. These vectors
included contrasts of upper versus lower body obesity and central versus peripheral
obesity. Fat patterning also has been described by using Z-scores to represent the
amount of adipose tissue at a specific site relative to the overall level of obesity,53
and it has been observed that women carry proportionately more fat on their legs
HEALTII RISKS OF OBESITY 119

than do men. 40 Obcse men exhibit a higher prevalcncc of decrcased glucosc

tolerance, hyperinsulinemia, hypertension, and hypertriglyccridcmia than do simi-
larly obese women. 96
On the assumption that adipose tissue at different locations could havc different
physiological functions or prognostic value, scveral ratios have been proposed to
describe body fat patterning. 64 In the 1940s and 1950s, Vaguc!." suggcsted that the
relative amount of uppcr (android) vcrsus lowcr (gynoid) body obcsity was important,
and could bc quantified by an average of two ratios, contrasting (1) fat at the nape
of the neck with that at the sacrum, and (2) the ratio of fat-to-muscle area in the
arm with that in the thigh. Hc further postulated that, although the gynoid obcsity
typically secn in women was bcnign, android obesity conferred an increascd risk of
diabetes, gout, and atherosclerosis. Android obcsity, dcfined on thc basis of Vague's
brachial-to-femoral adipose muscular ratio, subscquently has been shown to be an
important markcr for glucose intolcrancc, hypcrinsulincmia, and hypertriglycerid-
cmia. 91
In addition to android vcrsus gynoid obesity, other body fat patterns havc been
related to disease. Albrink and ,\1cigs 3 showcd that the thickness of the abdominal
skinfold was correlated more strongly with triglyccrides than was the triceps skinfold;
in addition, only skinfolds on the trunk correlated with the amount of wcight gained
in adulthood. Using ratios of various skinfold thickness measurements, Feldman's
team 48 subsequently showed that diabetic paticnts have a relative excess of fat on
the trunk. ,\1ore recently, subscapular skinfold thickncss has been shown to be
related more strongly to hypertension 16 146 and adverse lipid levcls'o than is the
triceps skinfold thickness.
The most consistent cross-sectional associations have been betwecn body fat
patterning and NIDDM. In addition to the studies ofVague '5S and Feldman,48 more
recent studies havc emphasized the importance of upper body and/or centrally
located fat in diabetes. Joos and colleagues,76 for cxamplc, found that diabetics have
relatively more subcutaneous fat in the subscapular region, but less in the calf, than
do nondiabetics. Comparcd with the triceps and ulnar skinfolds, the subscapular
skinfold thickness; (1) better differcntiates betwecn nondiabetics and diabetics; and
(2) more strongly correlates with fasting plasma glucose levels. 103 Furthcrmore, the
subscapular-to-triceps ratio also has been shown to be associated with NIDD,\1 in
women. 62 In other studies,76 howevcr, the triceps skinfold thickncss has provided
little predictive power for diabetes mellitus.
Prospective studies also have evaluated the importance of body fat patterning,
as assesscd by skinfold thickncss measurements. Subscapular skinfold thickness is a
better predictor of subscquent CVD than is either B,\1P6 154 or triceps skinfold
thickness. 154 Ducimeticrc and associates,39 using 13 skinfold sites in men, found that
subsequcnt coronary hcart discase could be prcdicted both by generalized obesity
and by a contrast of adipose tissuc on the trunk (mostly abdominal) versus that on
the thigh. Interestingly, as opposed to results of othcr prospectivc studics, a
significant relationship was seen after only 6.6 years of follow-up.
The distribution of adipose tissue also has been dcscribed by thc ratio of
circumference measurements: Both waist-to-hip (WHR)67 68 and waist-to-thigh S have
been used. Cross-sectional studies have shown that these ratios are associated with
menstrual abnormalities,67 hypertension," 68 and several mctabolic complications'"
57.67.76.90 Nevertheless, the most consistent associations again have becn observed
with diabetes mellitus, and WHR may be as important as the general degree of
overweight. Whereas the prcvalencc of diabetes was 5.5 times higher for women
in thc upper (versus lowcr) quartile of relativc weight, for example, it was 10.3
timcs as prevalcnt among women who wc re in thc upper quartiles of both relative
weight and WHR.67 Cilium'" also found that two indices of upper (versus lowcr)
body obesity, contrasting waist girth with an estimate of hip girth, were associated
120 AHMED H. KISSEBAI! ET AL.

with diabetes mellitus in a nationwide sample of adults in the United States.

Interestingly, insulin-dependent and noninsulin-dependent diabetic subjects appear
to have markedly different body fat distributions, with only the latter characterized
by central and upper body obesity. 105
Although the WHR is correlated moderately with Vague's classification of
android versus gynoid obesity,'36 it focuses primarily on abdominal obesity and is
as effective in predicting glucose and insulin levels as Vague's ratios or various
skinfold thickness measurements. 90 WHR shows only a weak correlation with the
ratio of subscapular-to-triceps skinfold thicknesses,61 and both ratios are associated
independently with triglyceride levels in men. 50 Circumference measurements show
less observer variability than do skinfold thickness measurements' and therefore are
more likely to be used widely.
Prospective studies have shown that WHR is predictive of subsequent diabetes
in men 123 and CVD in both men101 and women. OS The WHR is more predictive of
these endpoints than is either BMI or the sum of subscapular and triceps skinfolds,
and its effects are independent of the overall level of obesity. In view of the
conflicting findings of other prospective studies concerning generalized obesity and
CVD, it is interesting that WHR was the only anthropometric variable related
significantly to ischemic heart disease in a study of men. 10] Results from these
prospective studies also indicate that:
1. Waist-to-hip girth ratio is predictive of ischemic heart disease in persons equal to or
greater than 50 years of age at baseline. lQl
2. Significant associations were observed over a fairly short (12 to 13 years) follow-up
period.
3. Associations are strong enough to be observed in small samples of men (n = 855)101
and women (n = 1462).98
Furthermore, the risk of ischemic heart disease may be greatest in men who
are relatively lean (as defined by low BMI), but who have a high WHR. 101 This
partially may explain the U -shaped relationship observed in several studies 22 , 74. 82.
134.161,167 of overweight and ischemic heart disease: It is likely that some underweight
persons in these studies also had an upper body fat distribution.
The association between body fat distribution and female reproductive cancers
recently has been examined in 1462 women in the Gothenburg study.99 Baseline
levels of both subscapular skinfold thickness and WHR tended to be higher among
women who subsequently developed endometrial cancer than among women who
remained free of these cancers. In contrast, BMI showed a weaker relationship to
the incidence of endometrial cancer.

BIOLOGIC MECHANISMS ASSOCIATING BODY FAT

DISTRIBUTION WITH MORBIDITY

Studies have been pursued to define the major morphologic and metabolic
features that distinguish upper from lower body obesity and to evaluate their
relationship to health risks. These studies focused on three main questions:
1. Does body fat distribution detect abnormalities in the metabolic profile that are
predictive of morbidity?
2. What metabolic sequences are involved and how do they relate to obesity?
3. What factors determine body fat distribution and how does the regional fat depot
initiate deleterious metabolic events?
Relationship of Body Fat Distribution to the Metabolic Profile
To determine whether the site of body fat predominance predicts aberrations
in the metabolic profile, cohorts of premenopausal Caucasian women were evalu-
HEALTH RISKS OF OBESITY 121

Table 2. Correlation (r) of Body Fat Distribution to the Metabolic Profile

in Premenopausal Women
WHR ADJUSTED FOR WHRAND PER
WHR PER CENT lBW CENT lBW

Glucose and insulin

Glucose-Basal 0.42* 0.34* 0.54*
-Response to OGn 0.50* 0.33* 0.55*
Insulin-Basal 0.59* 0.45* 0.52*
-Response to OGn 0.51* 0.39* 0.57*
Fasting lipid and lipoproteins
Triglycerides 0.53* 0.38* 0.56*
Cholesterol 0.25* 0.17 0.56*
HDL-cholesterol -0.58* -0.42* -0.61*
HDLltotal cholesterol -0.56* -0.45* -0.64*
Blood pressure
Systolic 0.49* 0.42* 0.58*
Diastolic 0.41* 0.32* 0.56*
*p < 0.05 or less.
WHR = waist-to-hip girth ratio; lBW = ideal body weight; OGn oral glucose
tolerance test.

ated. 45, 46. 56. 78, 90, 91 The distribution of fat between the upper and lower body initially
was assessed using WHR. Table 2 shows that increasing WHR is accompanied by
progressively increasing fasting plasma glucose and insulin levels, and higher insulin
and glucose responses to oral glucose challenge. Fasting plasma levels of triglyceride
are increased and HDL-cholesterol decreased with increasing WHR, Partial and
multiple regression analysis revealed that the effects of body fat topography are
independent of and additive to those of obesity. Although WHR also correlates
with the plasma cholesterol level, this association depends on its correlation with
increasing relative body weight, Body fat distribution and the degree of obesity
independently and additively also are associated with increasing systolic and diastolic
blood pressure, Similar correlations have been reported in men,96
The waist-to-hip girth ratio has been found to be as effective in predicting the
metabolic profile as more complicated procedures, including multiple skinfold
thickness measurements, Vague's diabetogenic fat mass index, and Ashwell's fat
distribution score, Indeed, almost all anthropometric measures assessing the relative
distribution of fat between the trunk and the thigh, including the waist-to-thigh
circumference ratio and the subscapular-to-medial thigh skinfold ratio, predict the
metabolic profile equally well. l28 More important, however, is the significantly
higher association of the metabolic profile with the abdominal visceral fat mass
(determined by computed tomography scanning at the fourth lumbar vertebra) than
with total body fat (determined by underwater weighing method) (Table 3), This is
not entirely surprising because WHR correlates highly with the intra-abdominal
visceral fat mass.
The conclusions from these studies can be summarized as follows:
1. The WHR is a strong predictor of abnormalities in the metabolic profile
that predispose to health complications such as NIDDM and CVD.
2, The association of WHR with the metabolic abnormalities is independent of
and additive to effects of the degree of overweight.
3. The correlative power of WHR is the result of its prediction of the abdominal
visceral fat mass.
122 AHMED H. KISSEBAH ET AL.

Table 3. Relationship of Total Body and Visceral Fat to the Metabolic Profile
in Premenopausal Women
PER eEl'T
PER CENT VARIANCE (r')
VARIAl'CE (r') EXPLAI:\ED BY
EXPLAINED BY VISCERAL FAT
TOTAL FAT MASS VIASS

Glucose and insulin

Glucose-Basal 21.2 25.0
-Response to OGTT 16.0 27.6
Insulin-Basal 27.4 53.4*
-Response to OGTT 24.6 51.4*
Fasting lipids and lipoproteins
Triglycerides 32.2 60.0*
Cholesterol 4.7 3.8
HDL-cholesterol 3.0 10.5*
HDLltotal cholesterol 7.9 14.7*
Blood pressure
Systolic 14.2 27.4*
Diastolic 17.7 30.0*

*P < 0.05 or less compared to total fat mass.

OGTT = oral glucose tolerance test.

Metabolic Sequences Associating Body Fat Distribution

to Abnormalities in the Metabolic Profile
Glucose-insulin Homeostasis. The coexistence ofhyperinsulinemia and impaired
glucose tolerance in upper body segment obesity suggests that diminished insulin
sensitivity is the underlying abnormality. The in vivo insulin effects on overall
glucose metabolism have been assessed using the insulin impedance test and the
insulin euglycemic clamp procedure!6 129 The waist-to-hip girth ratio correlates
positively with the steady-state plasma glucose (SS PG) attained during the insulin
impedance test and negatively with the amount of glucose metabolized (:\1/1) during
the euglycemic clamp, determined at a steady-state plasma insulin of approximately
100 fLU per m!, suggesting diminished sensitivity of insulin-mediated glucose
disposal (Fig. 1).
Because skeletal muscle is a major source of glucose utilization, impaired
insulin sensitivity in this organ could play a primary role in the pathogenesis of

• •••
-
300 3 • (0.78, 4.72)

• •
l
r.O.80 r • .o.56
p eO.Ol peO.OS

.::- • •• •• •
~
g
200
•• • 2

• • •
••• ••
~ 100
~
• • ~
0 0
0.8 0.7 0.8 0.9 1.0 0.7 0.8 0.9 1.0

WHR w-R
Figure 1. Relationship of body fat distribution to in vivo insulin sensitivity. (SSPG =
steady-state plasma glucose attained during the insulin impedance test; M/I = glucose
metabolized relative to plasma insulin levels during the euglycemic clamp; WHR = waist-to-
hip girth ratio.)
HEALTH RISKS OF OBESITY 123

Table 4. Relationship of Obesity and Body Fat Distribution to

Prehepatic Insulin Production
II\SULII\ PRODUCTIO;\l RATE

Basal IV Glucose Oral Glucose

(mU/minim') (mUlminlm' ) (U/300 minim')

Nonobese 8.9 ± 1.4 60.0 ± 6.6 8.7 ± 1.7

Obese 35.4 ± 5.6* 166.3 ± 25.6* 21.8 ± 2.4*
WHR < 0.76 39.7 ± 9.4 184.7 ± 49.9 19.7 ± 3.7
WHR> 0.85 36.9 ± 7.6 177.4 ± 31.6 23.3 ± 3.9
*p < 0.05 or less compared to the nonobese.
IV = intravenous; WHR = waist-to-hip girth ratio.

diminished glucose disposal. As an index of insulin action in this organ, basal and
insulin-stimulated activities of glycogcn synthase I (CSI) were determined in
quadriceps muscle biopsies. 46 Insulin promotes glycogen deposition by increasing
per cent-CS I in skeletal muscle. Obese women, separated into three age- and
weight-matched subgroups by WHR, demonstrate that as WHR increases, the per
cent-CSI response to submaximal insulin levels declines significantly. This decline
is correlated highly with the impairment in overall glucose disposal. Insulin-specific
binding to circulating monocytes also is decreased as WHR increased. The decrease
in insulin binding is associated with the decline in skeletal muscle per cent-CSI
and the increase in SSPC.
Compared with the nonobese, obese women have greater prehepatic insulin
production basally and following intravenous or oral glucose stimulation. "9 In age-
and weight-matched upper and lower body segment obese subjects, however,
prehepatic insulin production is increased similarly (Table 4).
Figure 2 shows that, in the obese group, prehepatic production and portal
plasma levels of insulin are increased at all time-points during the oral glucose
stimulation. But no remarkable differences are observed between the upper and
the lower body obese subgroups. Insulin secretion thus appears to be influenced
markedly by total body fat but uninfluenced by the regional distribution of the
adipose mass.
Compared with nonobese, the upper body obese demonstrate a significant
decrease in hepatic insulin extraction both basally and during intravenous or oral
glucose stimulation (Table 5).'29 Increasing WHR also is correlated with a decreasing
hepatic insulin extraction fraction. Consequently, posthepatic insulin delivery is
increased, correlating well with thc increase in peripheral insulinemia. Further-
more, the diminished hepatic insulin extraction is proportionate to the decline in
insulin metabolic clearance rate and in the impairment of peripheral insulin
sensitivity accompanying upper body obesity. 129. 131
The insulin-stimulated glucose-utilization dose-response curve for the lower
body obese shows a rightward shift compared with that of the nonobese subject. 13'
The curve for the upper body obese exhibits a greater rightward shift and a marked
reduction of the maximal glucose utilization rate (Fig. 3). Compared with the
nonobese, the lower body obese dose-response curve for the insulin-mediated
suppression of hepatic glucose production also is shifted to the right, while the
curve for the upper body obese shows an even greater rightward shift. In both the
nonobese and the two obese subgroups, however, hepatic glucose production is
nearly completely suppressed at an insulin infusion rate of 40 mU per minute per
m' (Fig. 4). Obesity and body fat distribution thus influence glucose metabolism
via independent and additive mechanisms. An increase in relative body weight is
associated with a moderate decline in hepatic and peripheral insulin sensitivity.
124 AHMED H. KISSEBAH ET AL.

• OBESE SUBJECTS
• LEAN SUBJECTS
oo LOWER
UPPER BODY OBESE
BOOY OBESE

PORTAL VEIN INSULIN CONCENTRATION

•••• • • • • •
400 400

-i 300 300
Q::::~.~
~200 200
~
''0\.
100 100
"~·e;...e
030 10 110 240 300 030 10 180 240 300

PREHEPATIC INSULIN PRODUCTION

.;....
••• • • • • • •
120
JI·4 120

c ~ .......... \····6
i 10 80 \
~ ...
"E
:I
40
,
' ~
"""
.•....-i
..........-....
40 \\~'-e
0 0
030 10 ,., MO 300 030 10 110 240 300
Figure 2. Relationship of obesity and body fat distribution to insulin secretion rate and
portal vein insulin levels basally and following oral glucose stimulation.

Upper body fat localization is characterized by greater decreases in hepatic and

peripheral insulin sensitivity, as well as a marked reduction in maximal stimulation
of peripheral glucose utilization.
Figure 5 is a schematic diagram illustrating the interrelationship between
aberrations of insulin action and insulin dynamics in upper and lower body obesity.
Lower body obesity is associated with a mild decline in peripheral insulin sensitivity,

Table 5. Relationship of Obesity and Body Fat Distribution to

Hepatic Insulin Extraction
HEPATIC INSULIN EXTRACTION FRACTION (PER CENT)

Basal IV Glucose Oral Glucose

Nonobese 70 ± 3 49 ± 4 59 ± 6
Obese
WHR < 0.76 81 ± 4 50 ± 6 62 ± 4
WHR> 0.85 69 ± 3* 10 ± 2* 22 ± 5*
*p < 0.05 or less compared to lower body obese.
WHR < 0.76; IV = intravenous; WHR = waist-to-hip girth ratio.
HEALTH RISKS OF OBESITY 125

600

.......
N

C
E
500
.....
-D-

-0-
NonObese
Upper Body Obese
Lower Body Obese
'E 400
C,
§.

.. c
0 300

..
III
,~

::::>
Q)
200
UI
0
U

c:;
::J
100

0
10 100 1000 10000

Peripheral Arterialized Insulin Concentration (IlUlml)

Figure 3. Dose-response effects of insulin on glucose utilization. Relationship to obesity
and body fat distribution.

80

.......
N
.....
-D-

-0-
NonObese
Upper Body Obese
Lower Body Obese
E
C
'E 60
c,
§.

.. c
0
u 40

..
::J
"C
0
a..
Q)
UI
0 20
u
.a
(!)

10 100 1000

Portal Vein Insulin Concentration (IlUlml)

Figure 4. Dose-response effects of insulin on glucose production. Relationship to obesity
and body fat distribution.
126 AH'>IED H. KISSEBAH ET AL.

Figure 5. Relationship of body fat distribution to insulin sensitivity and insulin dynamics.

which is compensated for by an increase in pancreatic insulin production. Upper

body obesity is accompanied by a much more severe degree of insulin resistance,
an additional decline in hepatic insulin removal, and a greater degree of peripheral
hyperinsulinemia.
Not all abnormalities of glucose-insulin homeostasis in NIDDM, however, can
be explained by the presence of obesity and/or upper body fat predominance.
Additional defects, presumably related to genetic background, therefore must be
involved in the progression to NIDDM. The disturbance in glucose utilization in
upper body obesity is qualitatively and quantitatively similar to that observed in
NIDDM subjects. The development of overt hyperglycemia, however, coincides
with unsuppressed hepatic glucose production. Whether this additional defect
results from exhaustion of the beta cell insulin secretory capacity or a primary
disorder of hepatic glucose production is unknown. A summary of this interaction
is shown in Figure 6.
Lipoprotein Metabolism. In addition to the changes in plasma triglycerides,
total and HDL-cholesterol already discussed, individuals with upper body obesity
demonstrate metabolic and structural abnormalities in their plasma lipoproteins that
are indicative of increased coronary heart disease risk. Thus, in most obese subjects,
increased synthesis of very low density lipoprotein-triglycerides (VLDL-TC) and
VLDL apolipoprotein B (apo-B) is found. 41.59.01.88.138 The increase in VLDL-TC and
apo-B turnover rate is proportionate, resulting in increased secretion of VLDL
particles. The increase in VLDL production, however, is compensated for by a
comparable increase in its removal, and the efficiency of VLDL conversion to low
density lipoprotein (LDL) appears normal. Both the synthesis and removal of LDL
are increased. This pattern of increased VLDL and LDL flux is common in
individuals with upper body obesity and is found in other disorders with a high risk
for coronary heart disease, such as familial combined hyperlipidemia, hyperapobe-
talipoproteinemia, and NIDDM. 87 . 89 Upper body obesity also is associated with
increased plasma levels of small (dense) LDL and decreased levels of larger LDL
subspecies. There also are increased plasma levels of intermediate density lipopro-
tein (IDL) and small VLDL. The increased plasma concentration of these lipoprotein
subspecies is consistent with increased plasma flux of apo-B-containing lipoproteins
(VLDL, IDL, and LDL).
HEALTH RISKS OF OBESITY 127

FROM OBESITY TO DIABETES: ETIOLOGIC MECHANISMS

Degree of Overweight Upper Body Fat Localization

(Total Body Fat) (Abdominal or Visceral Fat)
Decreased peripheral and hepatic Similar but more pronounced
insulin sensitivity (non-rate-Iimiting
step)

Increased insulin secretion Decreased peripheral response to maximal

insulin concentrations (rate-limiting step)

Decreased hepatic insulin extraction

(rate-limiting step)

Genetic Predisposition
U nsuppressed hepatic glucose production
(rate-limiting step)

Decreased ins ulin secretion

Figure 6. Interaction between obesity and diabetes: Etiologic mechanisms.

Factors Influencing Body Fat Distribution and Mechanisms Associating

Regional Adiposity with the Metabolic Risk Factors
At the present time, this issue remains hypothetical. The prevailing view is
that body fat distribution and the accompanying metabolic abnormalities are linked
via an aberration in androgeniclestrogenic activity. Sensitivity to the androgenic
milieu is induced or exacerbated by a genetic and/or early developmental aberration
occurring at the time of sexual dimorphism.
In healthy, premenopausal women without significant history of hirsutism,
amenorrhea, or clinical evidence of endocrine disorders, no significant relationship
between body fat distribution and plasma level of total testosterone, androstenedi-
one, dihydroepiandrosterone sulfate, or estradiol is found. In contrast, there is a
highly significant trend toward a decrease in SHBG and an increase in percent-free
testosterone (FT) with increasing WHR (Fig. 7).56 Because plasma SHBG levels in
female humans are determined largely by the androgen to estrogen balance, the
decrease in SHBG and the increase in percent-FT thus indicate a relative increase
in androgenic activity.
The strong correlation between the increases in androgenic activity and WHR
suggests that body fat distribution might be a manifestation of the increased body
exposure to unbound androgens. The degree of androgenic activity (SHBG and
percent-FT) correlates with the increased adipocyte volumes in the abdomen but
not in the thigh, suggesting that hypertrophy of the abdominal adipocytes in the
upper body obese might also be a manifestation of hyperandrogenicity.56 Like men,
upper body obese women preferentially deposit fat intra-abdominally. gO Further-
more, in nonobese women with idiopathic hirsutism or polycystic ovarian disease,
the increased plasma androgen levels are associated with increased WHR. 43 Finally,
Rebuffe-Scrive 1l9 recently reviewed the regional morphologic and biochemical
characteristics of adipocytes from men and women. Her findings support the
hypothesis of regional specialization of the adipose tissue depots. Whereas the
femoral-gluteal depot primarily is a storage organ dedicated to such female stresses
as pregnancy and lactation, the abdominal visceral depot is dedicated primarily to
128 AHMED H. KrSSEBAH ET AL.

-
Te8toa- Andro8- % Free
Eatradlol terone tenedlone DHEA-S SHBG T88t08-
(ng/dl) (ng/dl) (ng/dl) (Ilg/dl) (llQIdl) terone
N8 NS NS NS -*
3.0

ImI NonobeM (n '" 19) = Obeee, WHR 0.111·0.85

(n = 27)
• ObeIe, WHR <0.111 _ Obeee, WHR >0.85
(n=12) (n .. za
Figure 7. Sex hormone balance in nonobese and obese women with varying body fat
distribution patterns.

storage of easily and rapidly mobilizable energy reserves. This anatomical and
functional specialization is governed by the sex hormone balance.
The growth potential of adipose tissue is contingent upon the number of cells
capable of accumulating fat (preadipocytes). If sex hormones are determinants of
body fat distribution, they also may influence regional recruitment and differentia-
tion of preadipocytes. Sexual maturation of the female rat is associated with
significant increases in the differentiated preadipocytes and fat cell number in all
regions. This increase is accompanied by a significant decrease in the undifferen-
tiated pool of preadipocytes in all depots except the femoral. In contrast to other
regions, the femoral depot possesses an infinite capacity to provide precursor cells
capable of rapid differentiation and transformation into mature adipocytes. This
characteristic appears to be maintained by ovarian factors. 93
In premenopausal women, the degree of androgenic activity correlates signifi-
cantly with the aberrations in plasma glucose and insulin levels. 56 Increasing
androgenic activity also correlated with decreasing peripheral insulin sensitivity
(Fig. 8) and the decline in hepatic insulin extraction (Fig. 9).130 These findings
suggest that the association between upper body fat localization, the aberrations in
hepatic insulin extraction and peripheral insulin sensitivity, and the resultant
changes in the metabolic profile, may be mediated by a common mechanism
involving the increase in androgenic activity. This contention is supported by the
finding of significantly impaired peripheral insulin sensitivity in nonobese hyper-
androgenized hirsute women. This impairment is overcome by administration of
the an tiandrogen, spironolactone. 43
Androgenic activity may influence glucose-insulin homeostasis via two additive
mechanisms. First, by influencing the deposition of adipocytes in areas around the
waist (visceral and subcutaneous) that are different morphologically and metabolically
from those deposited in the gluteofemoral region, androgens could result in
increased plasma free fatty acids (FFA) flux and overexposure of hepatic and
extrahepatic tissues to FF A. This mechanism is suggested by the following obser-
vations:
1. Upper body adipocytes are large and exhibit high rates of basal and
catecholamine-stimulated lipolysis, presumably caused by increased beta- to alpha-
adrenergic activities. 91
2. Upper body obese women demonstrate higher nocturnal levels of plasma
FFA, despite higher plasma insulin levels. 90
HEALTH RISKS OF OBESITY 129

(1.7. 4.1)-e . ,
"'" • , • •-<0.8. 4.1)

.......
(1.9. 5.5) (0.7. 5.5)
'E

.-
'"c i
i
E • E~
E ••• •••
·1·
••
2

- • • •
~ ~

• • •
......
po 0.54 ~ r- -0.49
pc 0.05 pc 0.05

0.. 1.0 U Ut u 0.7 Q.I 1.1 1.3 1.5 1.7

FT
"
SHBG
Figure 8. Relationship of sex hormone profile (SHBG and percent-FT) to insulin-
stimulated peripheral glucose utilization (M/I) in obese women with varying body fat
distribution patterns.

3. Feeding a high-fat diet to rats increases portal vein plasma FF A level and
hepatic triglyceride content, which correlates with a decline in hepatic insulin
extraction. 155
4. Animal and human studies suggest that FF A could inhibit insulin stimulation
of peripheral glucose metabolism and insulin suppression of hepatic glucose pro-
duction. 12. 49. 137
The second mechanism assumes that the androgenic activity might be directly
responsible for the abnormalities in insulin dynamics and in hepatic and extrahepatic
insulin actions. The influence of increased androgen activity on carbohydrate
metabolism is supported by the following observations:
1. When expressed per kg of lean body weight, insulin-mediated glucose
disposal, measured during the euglycemic clamp, is 45 per cent lower in healthy
men relative to women of similar age and body weight. 174

.0
, .0

•
:,
11 11

•
•• I . • • • •
"" 50 "" 50

...
~ ~
X X
I
~3I

20
• I• po 0.57
~ 31

20
• •• r- -0. S4
pc 0.05

• •
0.' 1.0 1••
pc 0.01

1.1 2.2
•
0,7 0..
I.
1.1 1.3 1.5
• '.7
SHBG " FT
Figure 9. Relationship of sex hormone profile (SHBG and percent-FT) to the hepatic
insulin extraction fraction (percent- HEF) in obese women with varying body fat distribution
patterns.
130 AH'-'IED H. KISSEllAH ET AL.

,,
_ _ _I . tInsulin Secretion
+
+Hepatic Insulin Extraction

Hyperinsulinemia

l
~peripheral Insulin Sensitivity~--------________~

Abdominal Adipocytes } -
(Subcutaneous and Visceral) t
Enhanced Plasma
+Recruitment Lipolysis - FFA Flux
+Size
tS/a Adrenergic Activity

Gluteofemoral Adipocytes ]
[ + Recruitment
+S/a Adrenergic Activity

Figure 10. Mechanisms associating hody fat distrihution and obesity to abnormalities in
insulin and glucose homeostasis.

2. Administration of testosterone derivatives to women results in impaired

glucose tolerance and hyperinsulinemia. 11,97
3. Hyperandrogenism and insulin resistance in women are associated with
polycystic ovary disease and acanthosis nigricans, and may abate with estrogen
therapy. 21,24
4. Experimental exposure of animals to encephalomyocarditis virus, strepto-
zotocin, or subtotal pancreatectomy results in a higher frequency of diabetes in
male than in female animals. Ill, 117, 125, 142
5. Estrogen administration reduces the activities of rat livcr gluconeogcnic
enzymes, alters the glucagon response, and promotes a decrease in plasma glucose, 110
Support for the influence of androgens on hepatic removal of insulin comcs
from the clevation of plasma insulin, but not c-peptide levels, in men compared
with age- and weight-matched women. ~3 Testosterone and insulin have similar
clearance rates, with approximately 50 per cent of each being removed from the
splanchnic circulation via the liver. Androgen receptors have been demonstrated in
the hepatic parenchymal cells of both rats and humans.145 Furthermore, studies in
sexually mature rats demonstrate that hepatic insulin extraction is lower in males
than in age- and weight-matched females. 114
The possible direct and indirect sites of interaction between androgenic activ-
ity and the abnormal metabolic profile in upper body obesity are summarized in
Figure 10.
The reasons for suggesting that the association between sex hormone balance,
body fat distribution, and metabolic abnormalities may be induced or exacerbated
by a genetic and/or early developmental aberration are as follows:
1. The association between body fat distribution and abnormalities in hepatic
insulin extraction or peripheral insulin sensitivity, when adjusted for the effects of
SHBG and percent-FT, although markedly reduced, are still detectable, suggesting
that the androgenic balance is not the sole determinant of these relationships. 130
2. In studies of nonobese hirsute women, plasma androgen levels are higher
than in upper body obese nonhirsute women, but the impairments in insulin-
mediated glucose metabolism are less pronounced. 127
HEALTH RISKS OF OBESITY 131

3. Treatment of hirsute women with the antiandrogen, spironolactone, nor-

malizes androgen levels and improves peripheral insulin sensitivity but does not,
consequently, normalize insulin-glucose homeostasisY
Why the liver and/or the peripheri should be sensitive to such small changes
in androgen levels remains obscure. Could the androgen sensitivity in upper body
obese women, in part, be caused by an aberrant sexual dimorphism? As reviewed
recently, animal studies'" have indicated the presence in the female liver of higher
levels of 5-alpha-reductase activity, which converts testosterone to its active metab-
olite, dihydrotestosterone. Sex-related differences in the hepatic metabolism of sex
steroids are known. 9 , 60 The relative abundance of hepatic androgen receptors also
is sex-dependent. These sexual differences in hepatic activities appear to be
imprinted by prenatal and neonatal exposure to sex steroids. No studies, however,
have addressed the relationship of sexual dimorphism to hepatic insulin processing
and insulin action.
Krotkiewski and Bjorntorp 95 demonstrated that upper body obese women, like
men, have a high preponderance of fast twitch fibers, while lower body obese
women resemble normal women, having a preponderance of slow twitch fibers in
their quadriceps muscle. Differences in insulin receptor number, substrate proc-
essing, and insulin sensitivity between muscle fiber types are well recognized.
Whether the characteristic muscle fiber composition in the upper body obese also
is part of an aberrant sexual dimorphism is unknown.
lJpper body obese individuals demonstrate a multitude of behavioral and
psychological maladjustments to stress. 14 They also suffer from menstrual irregular-
ities, suggesting the coexistence of a neuroendocrine disorder. Pre- and perinatal
exposure to androgens is known to influence behavior and maturation of the
neuroendocrine gonadal axis.42. 109 Could the neuroendocrine disorder in the upper
body obese also be part of aberrant sexual dimorphism? If so, to what extent and
by what mechanism could this disorder influence glucose-insulin homeostasis?
Finally, body fat distribution, in part, appears to be determined genetically, 19
and each of the metabolic complications associated with it, including NIDDYl,
hyperlipidemia, hypertension, and coronary heart disease, has a major genetic
component in its pathogenesis. Perinatal overexposure to androgens also might
result from a genetic disorder. To what extent these associations could be influenced
by genetic linkages is unknown.

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