Obesity Brief Lippincott's Illustrated Reviews Biochemistry, 3rd Edition ch26

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Obesity
I. OVERVIEW
Obesity results from a chronic disorder of appetite regulation and
energy metabolism, and is characterized by an accumulation of excess
body fat (see pxxx). In primitive societies, in which daily life requires a
high level of physical activity and food is only available intermittently, a
genetic tendency favoring storage of excess calories as fat has a sur-
vival value. However, the current abundance of food and reduced activ-
ity levels found in industrialized societies has resulted in a tendency for
the sustained deposition of fat. For example, this has caused an epi-
demic of obesity in the United States (Figure 26.1). The prevalence of
obesity increases with age and is more common among poorer persons
and in individuals with only a high school education or less. Particularly
alarming is the explosion of childhood obesity, which has shown a
three-fold increase in prevalence over the last two decades. Obesity is
not limited to the United States, but rather has increased globally. In
fact, by some estimates, there are more obese than undernourished
individuals worldwide. 
II. ASSESSMENT OF OBESITY
Obesity can often be diagnosed by a cursory physical examination.
However, monitoring of the disorder requires a quantitative estimate
of body fat. The amount of body fat is difficult to measure directly,
and is usually determined from an indirect measure—the body mass
index (BMI)—which has been shown to correlate with the amount of
body fat in most individuals. 
A. The body mass index
BMI gives a measure of relative weight, adjusted for height. This
allows comparisons both within and between populations. The BMI
is calculated in both men and women as follows:
BMI = (weight in kg)/ (height in meters)2
The normal range for the BMI is between 19.8 and 25.0. Individuals
with a BMI between 25.1 and 29.0 are considered overweight, those
whose BMI is greater than 30 are defined as obese. Nearly two-
thirds of American adults are overweight, and more than thirty per-
cent are obese (Figure 26.2). 
Figure 26.2
Nearly two thirds of American 
adults are overweight (BMI >25 
kg/m2) and more than thirty percent
are obese (BMI >30 kg/m2).
Total population
Obese (BMI >30)
Overweight (BMI >25) 
26
Lippincott’s Illustrated Reviews: Biochemistry, 3rd Edition
by Pamela C. Champe and Richard A. Harvey
Lippincott, Williams & Wilkins, Baltimore, MD  2003 1
Figure 26.1
Prevalence of obesity in adults,
ages 20 to 74 years, in the United
States.
30%
20%
10%
0%
1960-'62 1971-'74 1976-'80 1988-'94 1999-2000
 
B. Anatomical differences in fat deposition
The anatomical distribution of body fat has a major influence on
associated health risks. Excess fat located in the central abdominal
area of the body is called android, “apple shaped”, or upper body
obesity (Figure 26.3), and is associated with a greater risk for
hypertension, insulin resistance, diabetes, dyslipidemia, and coro-
nary heart disease (see p. xxx). It is defined as a waist to hip ratio of
more than 0.8 for women, and more than 1.0 for men. In contrast,
fat distributed in the lower extremities around the hips or gluteal
region is call gynoid, “pear shaped”, or lower body obesity. It is
defined as a waist to hip ratio of less than 0.8 for women and less
than 1.0 for men. The pear shape is relatively benign healthwise,
and is commonly found in females. 
C. Biochemical differences in regional fat depots 
The regional types of fat described above are biochemically differ-
ent. Abdominal fat cells are much larger and have a higher rate of
fat turnover than do lower body fat cells. The abdominal adipocytes
are also hormonally more responsive than are fat cells in the legs
and buttocks. Because men tend to accumulate the readily mobiliz-
able abdominal fat, they generally lose weight more readily than do
women, who accumulate lower body fat. Further, substances
released from abdominal fat are absorbed via the portal vein, and
thus have direct access to the liver. Fatty acids taken up by the liver
may lead to insulin resistance (see p. xxx) and increased synthesis
of triacylglycerols, which are released as VLDL (see p. xxx). By con-
trast, free fatty acids from gluteal fat enter the general circulation,
and have no preferential action on hepatic metabolism.
D. Number of fat cells 
When triacylglycerols are deposited in adipocytes, the cells initially
show a modest increase in size (Figure 26.4). However, the ability of
a fat cell to expand is limited, and when its maximal size is reached,
it divides. Most obesity is therefore thought to involve an increase in
both the number and size of adipocytes. Fat cells, once gained, are
never lost. Thus, when an obese individual loses weight, the size of
the fat cells is reduced, but the number of fat cells is not affected. An
obese individual, with increased numbers of adipocytes, will have to
reduce the size of those fat cells in order to normalize fat stores.
These individuals will be in the doubly abnormal state of having too
many, too small fat cells. This, in part, explains why formerly obese
patients have a particularly difficult time maintaining their reduced
body weight. The observation that fat cells are never lost empha-
sizes the importance of preventing obesity in the first place. 
III. BODY WEIGHT REGULATION
Body weight of most individuals tends to range within ten percent of a
set value. This observation prompted the theory that each individual
has a biologically predetermined “set point” for body weight. The body
attempts to add adipose tissue when the body weight falls below the set
Figure 26.3
Individuals more with upper body 
fat (left) have greater health risks
than pear-shaped individuals
(right).
Apple shaped =
upper body 
obesity
Pear shaped =
lower body 
obesity
WaistWaist
HipHip
2 26. Obesity
Figure 26.4
Hypertrophic versus hyperplastic
obesity.
Cell hyperplasia
(more cells)
Weight reduction is difficult after cell 
proliferation has occurred because 
the fat cells must become smaller 
than their normal size.
Cell hypertophy
(bigger cells)
Modest weight gain or loss in a 
non-obese person mainly affects
the size, but not the number of
adipocytes
 
point, and to lose weight when the body weight is higher than the set
point. For example, with weight loss, appetite increases and energy
expenditure falls; with overfeeding, appetite falls and energy expendi-
ture increases (Figure 26.5). However, a strict set point model fails to
explain why some individuals fail to revert to their starting weight after a
period of overeating, or the current epidemic of obesity. Body weight,
rather than being irrevocably set, seems to drift around a natural “set-
tling point” which reflects a balance between factors that influence food
intake and energy expenditure. In this context, body weight is stable as
long as the behavorial and environmental factors that influence energy
balance are constant.
A. Genetic contributions to obesity
Despite the widely held belief that obesity is a result of uncontrolled,
gluttonous eating behavior, it is now evident that genetic mecha-
nisms play a primary role in determining body weight, rather than a
lack of will power. For example, obesity is often observed clustered
in families. If both parents are obese, there is a seventy to eighty
percent chance of the children being obese. In contrast, only nine
percent of children were fat when both parents were lean. The
inheritance of obesity is not simple Mendelian genetics as would be
expected if the disease were due to a defect in a single gene.
Rather, obesity behaves as a complex polygenic disease involving
interactions between multiple genes and the environment. The
importance of genetics as a determinant of obesity is also indicatedby the observation that children who are adopted usually show a
body weight that correlates with their biologic rather than adoptive
parents Further, identical twins have very similar BMIs (Figure 26.6),
whether reared together or apart, and their BMIs are more similar
than those of nonidentical, dizygotic twins. It has been estimated
that between 25 percent and 70 percent of the variations in body
weight can be attributable to genetic factors. 
B. Environmental and behavioral contributions
The epidemic of obesity occurring over the last decade cannot be
explained by changes in genetic factors which are stable on this
short time scale. Clearly environmental factors, such as the ready
availability of palatable, energy-dense foods, plays a role in the
increased prevalence of obesity. Further, sedentary lifestyles
encouraged by TV watching, autos, computer usage, and energy-
sparing devices in the workplace and at home, decrease physical
activity and enhance the tendency to gain weight. The importance
of lifestyle in the development of obesity is reinforced by the obser-
vation that when Japanese or Chinese populations migrate to the
United States, their BMI increases. For example, men in Japan (age
46 to 49 years) are lean with an average BMI of 20, whereas
Japanese men of the same age living in California are heavier with
an average BMI of 24. Eating behaviors, such as snacking, portion
size, variety of foods consumed, an individual’s unique food prefer-
ences, and the number of people with whom one eats also influence
food consumption and tendency toward obesity.
Figure 26.6
Identical twins with combined
weight of 1300 pounds. Note
similarity in body shape.
III. Body Weight Regulation 3
Figure 26.5
Weight changes following episodes
of over- or underfeeding followed
by feeding with no restrictions.
under-
eating
Period 
of forced 
over-
eating
No restrictions
on food 
consumption
B
od
y 
w
ei
gh
t
B
od
y 
w
ei
gh
t
Starting weight
Starting weight
Body weight returns
to initial starting point 
after either experimental 
over- or underfeeding.
 
IV. MOLECULES THAT INFLUENCE OBESITY
The cause of obesity can be summarized in a deceptively simple state-
ment of the first law of thermodynamics: obesity results when energy
intake exceeds energy expenditure. However, unraveling the mecha-
nism underlying this imbalance involves a complex interaction of bio-
chemical, neurologic, environmental and psychological factors. For
example, appetite is influenced by afferent, or incoming signals—neural
signals, circulating hormones, and metabolites—that impinge on the
hypothalamus (Figure 26.7). These diverse signals prompt release of
hypothalamic peptides, and activate outgoing efferent neural signals.
Some of the important afferent signaling molecules regulating appetite
and energy consumption include:
A. Hormones of adipose tissue
Although the adipocyte’s primary role is to store fat, it also functions
as an endocrine cell that releases numerous regulatory molecules
such as leptin, adiponectin, and resistin. 
1. Leptin: Studies of the molecular genetics of mouse obesity have
led to the isolation of at least six genes that are associated with
obesity. Defects in the most well-known mouse gene, named Ob
(for obesity), which leads to severe hereditary obesity in mice, has
been identified and cloned. In one strain of fat mice, the gene was
completely absent indicating that the gene’s protein product is
required to keep the animals’ weight under control. The protein of
the Ob gene is a hormone called leptin. Leptin is produced pro-
portionally to the adipose mass, and thus informs the brain of the
fat store level (Figure 26.8). It is secreted by fat cells and acts on
the hypothalamus of the brain to regulate the amount of body fat
through the control of appetite and energy expenditure. Its secre-
tion is suppressed by depletion of fat stores (starvation) and
enhanced by expansion of fat stores (well fed state). Daily injec-
tion of leptin causes overweight mice to lose weight and maintain
weight loss. The protein also causes weight loss in mice that are
not obese. In humans, leptin increases metabolic rate and
decreases appetite. However, plasma leptin in obese humans is
4 26. Obesity
Figure 26.8
Action of leptin in maintaining adequate fat stores.
Hypothalamus
Adipose
Adipose
Efferent signals 
that increase food 
intake and
decrease energy 
expenditure
Efferent signals 
that maintain food
intake and energy
expenditure at
set point
Leptin Leptin
Starvation
Figure 26.7
Some afferent signals reflecting the
nutritional state of the body. CCK =
cholecystokinin.
 
Hypothalamus
STOMACH
ADIPOSE 
TISSUE
PERIPHERAL NERVOUS SYSTEM
CENTRAL NERVOUS SYSTEM
PANCREAS
INTES TINE
Efferent signals 
that influence 
appetite and 
energy 
expenditure
Afferent signals 
Insulin
Norepinephrine
Serotonin, 
dopamine, 
many others
Ghrelin
CCK
Leptin
 
usually normal for their fat mass, suggesting that resistance to
leptin, rather than its deficiency, occurs in human obesity. The
receptor for leptin in the hypothalamus has been cloned, and is
produced by a gene known as db. In rodents, mutation in the db
gene produces leptin resistance. However the mutations thus far
described in rodents do not appear to account for most human
obesity. Other hormones released by adipose tissue, such as
adiponectin and resistin, may mediate insulin resistance
observed in obesity.
B. Other hormones influencing obesity
Ghrelin, a peptide secreted primarily by the stomach, is the only
known appetite-stimulating hormone. Injection of ghrelin increases
short-term food intake in rodents, and may decrease energy expen-
diture and fat catabolism. Peptides, such as cholecystokinin (CCK),
released from the gut following ingestion of a meal can act as sati-
ety signals to the brain. Insulin not only influences metabolism, but
also promotes decreased energy intake. 
VI. METABOLIC CHANGES OBSERVED IN OBESITY
The metabolic abnormalities of obesity reflect molecular signals origi-
nating from the increased mass of adipocytes. The predominant effects
of obesity include dyslipidemias, glucose intolerance, and insulin resis-
tance, expressed primarily in the liver, muscle, and adipose tissue.
A. Metabolic syndrome
Abdominal obesity is associated with a threatening combination of
metabolic abnormalities that includes glucose intolerance, insulin
resistance, hyperinsulinemia, dyslipidemia (low HDL and VLDL),
and hypertension. This clustering of metabolic abnormalities has
been referred to as syndrome X, the insulin resistance syndrome,
or the metabolic syndrome. Individuals with this syndrome have a
markedly increased risk for developing diabetes mellitus and cardio-
vascular disorders. For example, men with the syndrome are three
to four times more likely to die of cardiovascular disease. 
B. Dyslipidemia
Insulin resistance in obese individuals leads to increased production
of insulin in an effort to maintain blood glucose levels. Insulin resis-
tance in adipose tissue causes increased activity of hormone-sensi-
tive lipase, resulting in increased levels of circulating fatty acids.
These fatty acids are carried to the liver and converted to triacyglyc-
erol and cholesterol. Excess triacyglycerol and cholesterol are
released as VLDL, resulting in elevated serum triacylglycerols
(Figure 26.9). Concomitantly, HDL levels are decreased.
VII. OBESITY AND HEALTH
Obesity is correlated with an increased risk of death (Figure 26.10) and
is a risk factor for a number of chronic conditions including adult onset
diabetes, hypercholesterolemia, high plasma triacylglycerols, hyperten-
VI. Obesity and Health 5
Figure 26.9
Body mass index and changes 
in blood lipids.m
m
o
l/l
Total cholesterol
Triacylglycerols
HDL-cholesterol0.8
1.6
2.4
5.8
6.6
0
20 24 28 32
Body mass index (kg/m2)
Figure 26.10
Body mass index and the relative 
risk of death. 
Men
Women
0
1.0
1.5
M
or
ta
lit
y 
ris
k
Body mass index (kg/m2)
HighLow ModerateVery 
low
30 35 4020 25
2.0
2.5
R: Is “visceral” obesity the same as “abdominal” obe-
sity? If so, let’s call it that and forget the “visceral”
 
sion, heart disease, some cancers, gallstones, arthritis and gout (Figure
26.11). The relationship between obesity and associated morbidities is
stronger among individuals younger than 55 years. After age 74, there is
no longer an association between increased BMI and mortality. Weight
loss in obese individuals leads to decreased blood pressure, serum tria-
cylglycerols and blood glucose levels. HDL levels increase. Mortality
decreased, particularly deaths due to cancer. Some obesity experts sug-
gest that moderately overweight and otherwise healthy individuals
should not obsess about weight loss, but rather should direct their ener-
gies to a healthier life style, particularly including some exercise in their
weekly routine. The increased mortality associated with individuals who
are only moderately overweight but otherwise healthy may result from a
sedentary lifestyle that is associated with obesity. For example, unfit,
lean men with BMIs of 25 or less have twice the risk of mortality from all
causes than fit overweight men with BMIs of 27.8 or greater.
VIII. WEIGHT REDUCTION
The goals of weight management in the obese patient are first, to
induce a negative energy balance to reduce body weight, that is,
decrease caloric intake and/or increase energy expenditure. The sec-
ond aim is to maintain a lower body weight over the longer term. 
A. Physical activity 
An increase in physical activity can create an energy deficit, and is
an important component of weight loss treatments. In addition,
physical activity increases cardiorespiratory fitness and reduces the
risk of cardiovascular disease, independent of weight loss. Persons
who combine caloric restriction and exercise with behavioral treat-
ment may expect to lose about five to ten percent of preintervention
body weight over a period of four to six months. Exercise is an
essential component of maintaining weight reduction.
B. Caloric restriction 
Dieting is the most commonly practiced approach to weight control.
Since one pound of adipose tissue corresponds to approximately
3500 kcal, one can estimate the effect of caloric restriction on the
reduction in adipose tissue. Weight loss on calorie restricted diets is
determined primarily by the energy intake and not nutrient composi-
tion. Caloric restriction is ineffective over the long term for many
individuals. More than ninety percent of people who attempt to lose
weight regain the lost weight once dietary intervention is sus-
pended. Nonetheless, it is important to recognize that although few
individuals will reach their ideal weight with treatment, weight losses
of ten percent of body weight over a six month period often reduces
blood pressure and lipid levels, and enhances control of type II dia-
betes. The health benefits of relatively small weight losses should
therefore be emphasized to the these patient.
C. Pharmacologic and surgical treatment
Two weight-loss medications are currently approved by the FDA for
use in adults who have a BMI of 30 or higher. The first, sibutramine1
6 26. Obesity
Figure 26.12
Weight loss for various therapeutic
regimines.
Pe
rc
en
t w
ei
gh
t l
os
s
Surgery
Months of treatment
Orlistat
Sibutramine
40
30
20
10
0
483624120
Figure 26.11
The relative risk of developing 
associated diseases in obese 
women and men compared to
non-obese individuals where the
risk = 1.0. 
Type 2 diabetes
Women
Men
12.7
5.2
2.6
4.2
1.5
3.0
3.2
2.7
Hypertension
Myocardial infarction
Colon cancer
1,2See chapter xxx in Lippincott’s Illustrated Reviews: Pharmacology (3rd ed.) 
for a more detailed discussion of drugs used to treat obesity.
INFO
LINK
 
is an appetite suppressant that inhibits the reuptake of both sero-
tonin and norepinephrine. The second, orlistat2 is a lipase inhibitor
that inhibits gastric and pancreatic lipases, thus decreasing the
breakdown of dietary fat into smaller molecules. Surgical proce-
dures designed to reduce food consumption are an option for the
severely obese patient who has not responded to other treatments
(Figure 26.12). Surgery produces greater and more sustained
weight loss than dietary or pharmacologic therapy, but has substan-
tial risks for complications.
IX. CONTENT SUMMARY
Obesity—the accumulation of excess body fat—results when energy
intake exceeds energy expenditure. Obesity is increasing in industrial-
ized countries because of a reduction in daily energy expenditure an
increase in energy intake resulting from the increasing availability of
palatable, energy dense food. Body mass index (BMI) is a measure of
VIII. Content Summary 7
Figure 26.13
Key concept map for obesity.
Assessment of body fat Accumulation of body fat
Amount of 
body fat
Normal
Over-
weight
ThighsHips
Higher than
normal risk
of mortality
and morbidity
Higher than normal
risk of mortality
and morbidity
Nearly normal 
risk of 
mortality and 
morbidity
(weight in kg)
(height in meters)2
 estimated by
Energy 
expenditure
< 20 20 
to 
25
>25
Obese
Under-
weight
Environmental 
 an behavior factors:
• Availability, cost, taste,
 variety, and energy-
 density of food
• Portion size
• Snacking
• Increased use of 
 automobiles,
 energy-saving 
 appliances, 
 televisions, 
 and computers
• Psychological or
 emotional response
 to food 
Chemical factors
• Leptin
• Serotonin 
• Dopamine 
• Ghrelin
• Cholecystokinin
• Norepinephrine
• Insulin
• Influence both
 food intake and
 energy expenditure
Genetic factors
• Many genes involved
• Influence both
 food intake and
 energy expenditure
results fromconsiders
>30
 associated with associated with
 greater than
Body mass index (BMI) 
 calculated by
 influenced by
Location of 
body fat Energy (food)
intake
 
26. Obesity
Study Questions
Choose the ONE best answer.
26.1 A 40-year-old woman, 5 feet 1 inch (155 cm) tall and
weighing 188 pounds (85.5 kg), seeks your advise on
how to lose weight. Her waist measured 41 inches
and hip measured 39 inches. A physical examination
and blood laboratory data were all within normal
range. Her only child, who is 14 years old, her sister,
and both of her parents are overweight. The patient
recalls being obese throughout her childhood and
adolescence. Over the past 15 years she had been
on seven different diets for periods of 2 weeks to
three months, losing from 5 to 25 pounds. Upon dis-
continuation of each diet, she regained weight,
returning to 185 to 190 pounds. Which one of the fol-
lowing best describes this patient.
A. She is classified as overweight.
B. She shows an “apple” (android) pattern of fat distri-
bution.
C. She has approximately the same number of fat
cells as a normal weight individual, but each
adipocyte is larger.
D. She would be expected to show lower than normal
levels of circulating leptin.
E. She would be expected to show lower than normal
levels of circulating triacylglycerols. 
The correct answer = B. Her waist to hip ratio is
39/40 = 0.98. Apple shape is defined as a waist
to hip ratio of more than 0.8 for women, and
more than 1.0 for men. She has, therefore, an
apple pattern of fat distribution, commonlyseen
in males. Compared with other women of the
same body weight who have a gynecoid fat pat-
tern, the presence of increased visceral or
intraabdominal adipose tissue places her at
greater risk for diabetes, hypertension, dyslipi-
demia and coronary heart disease. For this
patient BMI = weight (kg)/ height (m2) =
85.5/(1.55)2 = 35.6 kg/m2. The result indicates
that the patient is classif ied as obese.
Individuals with marked obesity and a history
dating to early childhood, have an adipose depot
made up of too many adipocytes each fully
loaded with triacyglycerols. Plasma leptin in
obese humans is usually normal for their fat
mass, suggesting that resistance to leptin, rather
than its deficiency, occurs in human obesity.
The elevated circulating fatty acids characteristic
of obesity are carried to the liver and converted
to triacyglycerol and cholesterol. Excess triacyg-
lycerol and cholesterol are released as VLDL,
resulting in elevated serum triacylglycerols. 
8
body fat. Nearly two thirds of American adults are overweight (BMI >25
kg/m2) and more than thirty percent are obese (BMI >30 kg/m2). Excess
fat located in the central abdominal area of the body is associated with
greater risk for hypertension, insulin resistance, diabetes, dyslipidemia
and coronary heart disease than is fat located in the hip and thighs. The
body attempts to add adipose tissue when the body weight falls below a
set point, and to lose weight when the body weight is higher than the
set point, The weight is determined by genetic and environmental fac-
tors. Appetite is influenced by afferent, or incoming signals—neural sig-
nals, circulating hormones, and metabolites—that impinge on the
hypothalamus. These diverse signals prompt release of hypothalamic
peptides and activate outgoing efferent neural signals. Some of the
important afferent signaling molecules regulating appetite and energy
consumption include leptin, adiponectin, resistin, and ghrelin. Obesity
is correlated with an increased risk of death, and is a risk factor for a
number of chronic conditions. Weight reduction is achieved with nega-
tive energy balance to reduce body weight, that is, decreasing caloric
intake and/or increasing energy expenditure. Virtually all diets that limit
particular groups of foods or macronutrients lead to short-term weight
loss. Long-term maintenance of weight loss is difficult to achieve.
Modest reduction in food intake occurs with pharmacologic treatment.
Surgical procedures designed to reduce food consumption are an
option for the severely obese patient who has not responded to other
treatments.