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HE EFFECTS OF excess weight on morbidity and mortality have been known for more than 2000 yr. Hippocrates recognized that sudden death is more common in
those who are naturally fat than in the lean, and Malcolm
Flemyng in 1760 observed that corpulency, when in an
extraordinary degree, may be reckoned a disease, as it in
some measure obstructs the free exercise of the animal functions; and hath a tendency to shorten life, by paving the way
to dangerous distempers.
Obesity is a chronic disease in the same sense as hypertension and atherosclerosis. The etiology or cause of
obesity is an imbalance between the energy ingested in
food and the energy expended. The excess energy is stored
in fat cells that enlarge and/or increase in number. It is this
hyperplasia and hypertrophy of fat cells that is the pathological lesion of obesity. Enlarged fat cells produce the
clinical problems associated with obesity either because of
either the weight or mass of the extra fat or because of the
increased secretion of free fatty acids and numerous peptides from enlarged fat cells. The consequence of these two
mechanisms is other diseases, such as diabetes mellitus,
gallbladder disease, osteoarthritis, heart disease, and some
forms of cancer. The spectrum of medical, social, and
psychological disabilities includes a range of medical and
behavioral problems.
Abbreviations: apo, Apolipoprotein; BMI, body mass index; CHD,
coronary heart disease; HDL, high-density lipoprotein; LDL, lowdensity lipoprotein; NAFLD, nonalcoholic fatty liver disease; VLDL,
very LDL.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
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FIG. 1. The pathology of obesity produces the myriad of health related problems. These health-related problems can be attributed to
either the increased mass of fat or the increased release of peptides
from enlarged fat cells. CVD, Cardiovacular disease; GB, gallbladder.
Increased visceral fat enhances the degree of insulin resistance associated with obesity and hyperinsulinemia. Together, hyperinsulinemia and insulin resistance enhance the
risk of the comorbidities described below.
Diseases associated with increased fat mass
Defining level
a
The syndrome is present if an individual has any three of the
following five criteria.
hyperinsulinemic clamp. The hyperinsulinemia, in turn, increases hepatic very low density lipoprotein (VLDL) triglyceride synthesis and secretion, increases plasminogen activator inhibitor-1 synthesis, increases sympathetic nervous
system activity, and increases renal sodium reabsorption.
Insulin resistance is the hallmark of the metabolic (or dysmetabolic) syndrome. The National Cholesterol Education
Program Adult Treatment Panel III has recently provided
defining values for this syndrome (Table 1). When three of
the five criteria listed in table are abnormal, the patient has
the metabolic syndrome. A central feature of this syndrome
is increased visceral fat. This increased release of free fatty
acids impairs insulin clearance by the liver and altered peripheral metabolism. The reduced production of adiponectin
by the fat cell is another potential player in the development
of insulin resistance.
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis. NAFLD is the term that describes a constellation
of liver abnormalities associated with obesity, including hepatomegaly, elevated liver enzymes, and abnormal liver histology, such as steatosis, steatohepatitis, fibrosis, and cirrhosis (13). A retrospective analysis of liver biopsy specimens
obtained from overweight and obese patients with abnormal
liver biochemistries, but without evidence of acquired, autoimmune, or genetic liver disease, demonstrated a 30%
prevalence of septal fibrosis and a 10% prevalence of cirrhosis (14). Another study using a cross-sectional analysis of
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diac reserve, especially in the presence of hypertension. Interestingly, heart rate was well within normal limits.
Central fat distribution is associated with small, dense low
density lipoproteins (LDL) as opposed to large, fluffy LDL
particles (23). For a similar level of cholesterol, the risk of
coronary heart disease (CHD) is significantly higher in individuals with small dense LDL than in those with large
fluffy LDL. Because each LDL particle has a single molecule
of apolipoprotein B (apo B) protein, the concentration of apo
B can be used to estimate the number of LDL particles.
Despres et al. (23) demonstrated that the level of apo B is a
strong predictor of the risk for CHD. Based on a study of
French Canadians, these researchers proposed that estimating apo B, the levels of fasting insulin, the concentration of
triglyceride, the concentration of HDL cholesterol, and waist
circumference could help identify individuals at high risk for
the metabolic syndrome and coronary heart disease.
Cancer. Certain forms of cancer are significantly increased in
overweight individuals (21, 24). Males face increased risk for
neoplasms of the colon, rectum, and prostate. In women,
cancers of the reproductive system and gallbladder are more
common. One explanation for the increased risk of endometrial cancer in overweight women is the increased production
of estrogens by adipose tissue stromal cells. This increased
production is related to the degree of excess body fat that
accounts for a major source of estrogen production in postmenopausal women. Breast cancer is not only related to total
body fat, but also may have a more important relationship
to central body fat (25). The increased visceral fat measured
by computed tomography shows an important relationship
to the risk of breast cancer.
Endocrine changes. A variety of endocrine changes are associated with overweight (Table 2). The changes in the reproductive system are among the most important. Irregular
menses and frequent anovular cycles are common, and the
rate of fertility may be reduced (26). Some reports describe
increased risks of toxemia. Hypertension and cesarean section may also be more frequent. Irregular menses, amenorrhea, and infertility are associated with obesity (27). Women
with a BMI greater than 30 kg/m2 have abnormalities in
secretion of hypothalamic GnRH, pituitary LH, and FSH,
which results in anovulation (28).
Obesity shortens life
The net effect of the increased fat mass and the enlarged
fat cells is a decrease in life expectancy that is detailed below.
TABLE 2. Endocrine changes associated with obesity
Increased
Decreased
Leptin in plasma
TSH (upper normal range)
Insulin
IGF-I
Androgens
Progesterone
Cytokines (IL-6)
ACTH/cortisol
Sympathetic nervous system activity
GH
Ghrelin
Adiponectin
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JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
endocrine community.