Obesity

Last Updated: June 17, 2004

Synonyms and related keywords: overweight, increased BMI,

excess body fat, excess adiposity, increased body mass index,
Quetelet index, POMC, MC4, satiety, weight loss, weight gain,
gastric bypass
AUTHOR INFORMATION

Section 1 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Followup Miscellaneous Pictures Bibliography

Author: Gabriel I Uwaifo, MBBS, Clinical and Research

Attending, Assistant Professor of Medicine and Endocrinology,
MedStar Clinical Research Center, The MedStar Research
Institute and the Washington Hospital Center
Coauthor(s): Elif Arioglu, MD, Assistant Professor of Medicine,
Division of Endocrinology and Metabolism, University of
Michigan
Gabriel I Uwaifo, MBBS, is a member of the following medical
societies: American Association of Clinical Endocrinologists,
American College of Physicians-American Society of Internal
Medicine, American Diabetes Association, American Medical
Association, American Society of Hypertension, and Endocrine
Society
Editor(s): Harris C Taylor, MD, Chief, Division of
Endocrinology, Lutheran Medical Center of Cleveland; Clinical
Professor, Department of Internal Medicine, Case Western
University School Of Medicine; Francisco Talavera, PharmD,
PhD, Senior Pharmacy Editor, eMedicine; Romesh Khardori,
MD, Chief, Division of Endocrinology, Metabolism and
Molecular Medicine, Professor, Department of Internal Medicine,
Southern Illinois University School of Medicine; Mark Cooper,
MD, Head, Vascular Division, Baker Medical Research Institute;
Professor of Medicine, Monash University; and Michael E
Zevitz, MD, Assistant Professor of Medicine, Finch University of
the Health Sciences, The Chicago Medical School; Consulting
Staff, Private Practice
Disclosure

INTRODUCTION

Section 2 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Followup Miscellaneous Pictures Bibliography

Background: Obesity is a significant public health crisis in the

United States and the rest of the developed world. The prevalence is
also increasing rapidly in numerous developing nations worldwide.
This growing incidence represents a pandemic that needs urgent
attention if the potential morbidity, mortality, and economic tolls that
will be left in its wake are to be avoided.
The cost of obesity management in the United States alone amounts
to approximately $100 billion annually, of which approximately $52
billion are from the direct costs of health care. These costs amount to
approximately 5.7% of the entire US health expenditure. The cost of
lost productivity due to obesity amounts to approximately $3.9
billion, while another $33 billion is spent annually on various weight
loss products and services.
Obesity represents a state of excess storage of body fat. Although
very similar, the term overweight puristically is defined as an excess
body weight for height. While adult men have a body fat percentage
of 15-20%, women have a higher proportion (approximately 2530%). Because differences in weight among individuals are only
partly due to body fat variations, body weight is a rather limited,
although easily obtained, index of obesity.
The body mass index (BMI), also known as the Quetelet index, is far
more commonly used to define obesity and has been found to closely
correlate with the degree of body fat in most settings. BMI = (weight
[kg]) / (height [m])2. The body fat percentage can be estimated using
the Deurenberg equation. Body fat percentage = 1.2(BMI) +
0.23(age [y]) 10.8(sex) 5.4, with males coded as 1 and females as
0. This formula has a standard error of 4% and explains
approximately 80% of the variation in body fat.
Other indices used to estimate the degree and distribution of obesity
include the 4 standard skin thicknesses (ie, subscapular, triceps,
biceps, suprailiac) and various anthropometric measures, of which
waist and hip circumferences are the most important.
While several accepted classifications and definitions exist for
degrees of obesity, the most widely accepted is the World Health
Organization (WHO) criteria based on BMI. Under this convention
for adults, grade 1 overweight (commonly and simply called
overweight) is a BMI of 25-29.9 kg/m2. Grade 2 overweight

(commonly called obesity) is a BMI of 30-39.9 kg/m2. Grade 3

overweight (commonly called severe or morbid obesity) is a BMI
greater than or equal to 40 kg/m2.
The surgical literature often uses a different classification in order to
recognize particularly severe obesity. In this setting, a BMI greater
than 40 kg/m2 is described as severe obesity, a BMI of 40-50 kg/m2
is termed morbid obesity, and a BMI greater than 50 kg/m2 is termed
super obese.
The definition of obesity in children involves BMIs greater than the
85th (commonly used to define overweight) or the 95th (commonly
used to define obesity) percentile, respectively, for age-matched and
sex-matched controls.
Apart from total body fat mass, accumulating data suggest that
regional fat distribution also has significant impact on the incidence
of comorbidities associated with obesity. Higher abdominal fat
content (including visceral and, to a lesser extent, subcutaneous
abdominal fat) is strongly correlated with worse metabolic and
clinical consequences of obesity. As a result, android obesity, which
is predominantly abdominal, is more predictive of adipose-related
comorbidities than gynecoid obesity, which has a more peripheral
(gluteal) distribution. For men, waist circumferences greater than 94
cm (>80 cm in women) and waist-to-hip ratios greater than 0.95 cm
(>0.8 cm in women) indicate a threshold of significantly increased
potential cardiovascular risk. Circumferences of 102 cm in men and
88 cm in women indicate a markedly increased potential risk
requiring urgent therapeutic intervention.
Obesity is associated with a host of potential comorbidities that
significantly increase the potential morbidity and mortality
associated with the condition. While a cause and effect relationship
has not been exhaustively demonstrated for all these comorbidities,
amelioration of these conditions with significant weight loss
suggests that obesity probably plays a significant role in their
development.
The adipocyte, which is the cellular basis for obesity, is being found
to be an increasingly complex and metabolically active cell.
Currently, the adipocyte is being perceived more frequently as an
endocrine gland with several peptides and metabolites that may have
relevance to the control of body weight, and these currently are
being studied intensively. Among the products of the adipocyte
involved in the complex intermediary metabolism are the cytokines,

tumor necrosis factor-alpha, interleukin-6, lipotransin, adipocyte

lipid-binding protein, acyl stimulation protein, prostaglandins,
adipsin, perilipins, lactate, adiponectin, monobutyrin, and
phospholipid transfer protein.
Among the critical enzymes involved in adipocyte metabolism are
endothelial lipoprotein lipase (involved in lipid storage), hormonesensitive lipase (involved in lipid elaboration and release from
adipocyte depots), acylcoenzyme A (acyl-CoA) synthetases
(involved in fatty acid synthesis), and a cascade of enzymes
(involved in beta oxidation and fatty acid metabolism). The ongoing
flurry of investigation into the intricacies of adipocyte metabolism in
the last 5 years has not only improved our understanding of the
pathogenesis of obesity but also has offered multiple potential targets
for therapy.
Another area of actively progressing research is the cues for the
differentiation of preadipocytes to adipocytes. With the fairly recent
recognition that this process occurs in both white and brown adipose
tissue of even adults, its potential role in the development of obesity
and the relapse to obesity after weight loss has become more
important. Among the presently identified factors involved in this
process are the transcription factors peroxisome proliferatoractivated receptors gamma (PPAR-gamma), the retinoid-X receptor
ligands, perilipin, adipocyte differentiation-related protein (ADRP),
and CCAAT enhancer-binding proteins (C/EBP) alpha, beta, and
delta.
Pathophysiology: The pathogenesis of obesity is far more complex
than the simple paradigm of an imbalance between energy intake and
energy output. Although this concept allows easy conceptualization
of the various mechanisms involved in the development of obesity,
obesity obviously is far more than the mere result of excess eating
and/or too little exercise. However, the prevalence of inactivity in
developed countries is significant and relevant. In the United States,
only approximately 22% of adults and 25% of adolescents report
significant regular physical activity. Approximately 25% of adults in
the United States report no significant physical activity during
leisure, while approximately 14% of adolescents have similar reports
of inactivity.
Two major groups of factors with a balance that variably intertwines
in the development of obesity are genetics, which is presumed to
explain 40-70% of the variability in obesity variance, and
environmental factors. While the high prevalence of obesity in the

children of parents who are obese and the high concordance of

obesity in identical twins suggest a significant genetic component to
the pathogenesis of obesity, the secular trends of the last few
decades, which are coincident with recent changes in dietary habits
and activity, also suggest a significant role for environmental factors.
Leptin
Leptin was discovered in 1994 by Friedman et al and ushered in an
explosion of research and a great increase in knowledge about
regulation of the human feeding and eating cycle. Since this
discovery, the neuromodulation of satiety and hunger with feeding
clearly is far more complex than the simplistic older model of the
ventromedial hypothalamic nucleus and limbic centers of satiety and
the feeding centers of the lateral hypothalamus. Leptin is a 16 kd
protein produced predominantly in white adipose tissue and, to a
lesser extent, in the placenta, skeletal muscle, and stomach fundus in
rats. Leptin has a myriad of functions in carbohydrate, bone, and
reproductive metabolism that are still being unraveled, but its role in
body weight regulation forms the major claim to fame (leptin from
the Greek word leptos, meaning thin).
The major role of leptin in body weight regulation is to signal satiety
to the hypothalamus and, thus, reduce dietary intake and fat storage
while modulating energy expenditure and carbohydrate metabolism
to prevent further weight gain. Unfortunately, unlike the Ob/Ob
mouse model in which this peptide was first characterized, most
humans who are obese are not leptin-deficient but rather leptinresistant and, thus, have elevated circulating leptin levels. While
most human obesity is polygenic (>90% of cases), the recognition of
monogenic variants has greatly enhanced our knowledge about the
etiopathogenesis of obesity.
Monogenic models for obesity in humans and experimental
animals
The various available monogenic models have greatly increased our
knowledge about mechanisms for the development of obesity, and
they also have provided multiple potential targets for future
antiobesity medications.
Proopiomelanocortin (POMC) and alphamelanocyte-stimulating
hormone (alpha-MSH) both act centrally on the melanocortin
receptor 4 (MC 4) to reduce dietary intake. Genetic defects in POMC
production and mutations in the MC4 gene both have been described

as monogenic causes of obesity in humans. Of particular interest is

the fact that patients with POMC mutations, because of the
deficiency in MSH production that results, tend to have red-colored
hair. Also, because of their diminished adrenocorticotropic hormone
(ACTH) levels, they tend to have central adrenal insufficiency. Some
recent data suggest that as many as 5% of children who are obese
have MC4 or POMC mutations. If confirmed, these would be the
most common identifiable genetic defects associated with obesity in
humans (band 2p23 for POMC and band 18q21.3 for MC4).
The Ob/Ob mice are the prototypical mice that set the stage for the
discovery of leptin. These mice lack the leptin gene and are
overweight and hyperphagic. A few humans have been identified
who have a similar genetic defect with similar phenotypic
consequences. This variant of obesity, although minor in the grand
scheme of human obesity, is exquisitely sensitive to leptin injection,
with reduced dietary intake and profound weight loss (band 7q31).
The Db/Db mice have mutations of the leptin receptor in the
hypothalamus. Fa/Fa mice also have leptin-receptor mutations.
These mice have early-onset obesity and hyperphagia like the Ob/Ob
mice, but they also have normal or elevated leptin levels. Human
counterparts of this model are very rare and are associated with
hyperphagia, hypogonadotrophic hypogonadism, and defective
thyrotropin secretion, but they are not associated with
hypercortisolism, hyperglycemia, and hypothermia as occurs in
Db/Db mice (band 1p31). The leptin receptor is one of the cytokine
receptor families of receptors and is activated through the Janus
kinases/signal transducers and activators of transcription
(JAK/STAT) mechanisms.
Prohormone convertase is an enzyme that is critical in protein
processing, and it appears to be involved in the conversion of POMC
to alpha-MSH. Patients identified to have this, although rare, have
significant obesity, hypogonadotrophic hypogonadism, and central
adrenal insufficiency. It is one of the few obesity models not
associated with insulin resistance (band 5q15-21).
PPAR-gamma is a transcription factor that is involved in adipocyte
differentiation. All humans with mutations of the receptor described
so far have severe obesity (band 3p25).
In addition to the above monogenic models of obesity, genome-wide
linkage analyses and microarray technology have revealed a rapidly
growing list of potential susceptibility obesity genes. Among those

identified that are being actively studied are genes on chromosome

arms 2p, 10p, 5p, 11q, and 20q.
In the same line as the evidence that proved Helicobacter pylori as
the cause for peptic ulcer disease, some evolving data suggest that a
significant inflammatory and possibly infective etiology may exist
for obesity. Adipose tissue is known to be a repository of various
cytokines, especially interleukin-6 and tumor necrosis factor-alpha.
Some data have shown that adenovirus 36 infection is associated
with obesity in chickens and mice. Other data also suggest that while
humans who are not obese have a 5% prevalence rate of adenovirus
36 infection, humans who are obese have a prevalence rate of 2030%.
Frequency:

In the US: Estimates suggest that approximately 100 million

adults in the United States are at least overweight or obese.
Approximately 35% of women and 31% of men older than
19 years are obese or overweight. The numbers among
children are even more imposing. The prevalence of obesity
in children in the United States has increased markedly
between the time of the National Health and Nutrition
Examination Survey (NHANES) 2 and 3 trials.
Approximately 20-25% of children are either overweight or
obese, and the prevalence is even greater in some minority
groups, including Pima Indians, Mexican Americans, and
African Americans. Conservative estimates suggest that the
management of obesity consumes approximately $100 billion
yearly, without factoring in the costs of various commercial
dietary and weight loss programs.

Internationally: The prevalence of obesity worldwide is

increasing, and this is particularly occurring in the developed
nations of the Northern Hemisphere, including the United
States, Canada, and most of Europe. Available data from the
MONICA (monitoring cardiovascular) disease study in
Europe suggest that at least 15% of men and 22% of women
in Europe are obese.

Similar data now are being reported from many developing

countries, particularly in Asia and, to a lesser extent, in
Africa. Reports from countries such as Malaysia, Japan,
Australia, New Zealand, and China detail an epidemic of
obesity in the last 2-3 decades. Data from the Middle Eastern

countries of Bahrain, Saudi Arabia, Egypt, Jordan, Tunisia,

and Lebanon, among others, exhibit this same disturbing
trend, with alarming levels of obesity often exceeding 40%,
particularly worse in women. Data from the Caribbean and
South America also highlight similar trends. While data from
Africa on this issue are scant, a clear and distinct secular
trend of profoundly increased BMIs clearly exists when
people from Africa immigrate to northwestern hemispheric
countries. Studies comparing these indices among Nigerians
residing in Nigeria and recent immigrants to the United
States show this trend very poignantly.

Conservative estimates suggest that as many as 250 million

people (approximately 7% of the estimated current world
population) are obese. Two- to three-times more people
probably are overweight. While a negative correlation
between socioeconomic class and obesity prevalence exists
in most developed countries, including the United States, a
distinct reversal in this correlation exists in many lessdeveloped areas, including China, Malaysia, parts of South
America, and sub-Saharan Africa.

Mortality/Morbidity:

Data available from insurance company databases and large

prospective cohorts such as the Framingham and NHANES
studies clearly indicate that obesity is associated with a
significant increase in both morbidity and mortality.

The mortality data appear to have a U-shaped or J-shaped

conformation in relation to weight distribution. The degree of
obesity (generally indicated by the BMI) at which a
discernible increase in mortality occurs is, however, higher
for African Americans and Hispanic Americans than for
white Americans, suggesting a significant racial spectrum
and difference in this effect.

Race:

Obesity is a cosmopolitan disease that affects all races

worldwide. However, certain ethnic and racial groups appear
to be particularly predisposed. The Pima Indians of Arizona
and other ethnic groups native to North America have a
particularly high prevalence of obesity. In addition,
Polynesians, Micronesians, Anurans, Maoris of the West and
East Indies, African Americans in North America, and the
Hispanic populations (both Mexican and Puerto Rican in

origin) in North America also have particularly high

predispositions to developing obesity.

Secular trend studies clearly underline the marked

importance of environmental factors (particularly dietary
issues) in the development of obesity. Many of the
genetically similar cohorts of the above named high-risk
ethnic and racial groups have far less prevalence for obesity
in their countries of origin, but this changes significantly
when such groups have immigrated to the affluent Northern
Hemisphere, with altered dietary and activity habits. These
findings form the core concept of the thrifty gene hypothesis
espoused by Neal et al.

Sex:

No significant sex difference exists in the prevalence of

obesity.

Age:

The prevalence and age distribution of obesity has changed

significantly in the last 2-3 decades.

While the prevalence has remained at 30-50% of the adult

population in the United States, the prevalence in children
has increased to 15-25%.

Clearly evidenced in secular trends, children (particularly

adolescents) who are obese have a very high probability of
growing to be adults who are obese; hence, this bimodal
distribution of obesity portends a large-scale obesity
epidemic in the next few decades.

CLINICAL

Section 3 of 11

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History: In most patients, the presentation is straightforward, with

the patient indicating problems with weight or repeated failure in
achieving sustained weight loss. However, in other cases, the subject
may present with complications and/or associations of obesity (see

Image 1).

A full history must include a dietary inventory and an

analysis of the subject's activity level.

Screening questions to exclude depression are vital because

this may be a consequence or a cause of excessive dietary
intake and reduced activity.

Because almost 30% of patients who are obese have eating

disorders, screen for this in the history. The possibility of
binging, purging, lack of satiety, food-seeking behavior, and
other abnormal feeding habits need to be identified because
management of these habits is crucial to the success of any
weight management program.

Also, investigate whether any of the previously mentioned

comorbidities have occurred, and include questions to
exclude the possible rare causes of secondary obesity (see
Image 2).

When asking patients about their history, investigate whether

the rest of the patient's family also has weight problems,
inquire about the expectations of the subject, and estimate the
level of motivation of the subject.

Comorbidities related to obesity include the following (also

see Image 1):
o

Cardiovascular - Essential hypertension, coronary

artery disease, left ventricular hypertrophy, cor
pulmonale, obesity-associated cardiomyopathy,
accelerated atherosclerosis, pulmonary hypertension
of obesity

Central nervous system - Stroke, idiopathic

intracranial hypertension, meralgia, paresthetica

Gastrointestinal - Gall bladder disease (cholecystitis,

cholelithiasis), nonalcoholic steatohepatitis (NASH),
fatty liver infiltration, reflux esophagitis

Respiratory tract - Obstructive sleep apnea, obesity

hypoventilation syndrome (Pickwickian syndrome),
increased predisposition to respiratory infections,

increased incidence of bronchial asthma

o

Malignancies - Association with endometrial,

prostate, gall bladder, breast, colon, and, possibly,
lung cancer

Psychologic - Social stigmatization, depression

Orthopedic - Osteoarthritis, coxa vera, slipped capital

femoral epiphyses, Blount disease and Legg-CalvPerthes disease, chronic lumbago

Metabolic - Insulin resistance, hyperinsulinemia, type

2 diabetes mellitus, dyslipidemia (characterized by
high total cholesterol, high triglycerides, normal or
elevated low-density lipoprotein, and low highdensity lipoprotein)

Reproductive - Anovulation, early puberty, infertility,

hyperandrogenism and polycystic ovaries in women,
hypogonadotrophic hypogonadism in men

Obstetric and perinatal - Pregnancy-related

hypertension, fetal macrosomia, pelvic dystocia

Increased surgical risk and postoperative

complications including wound infection, deep
venous thrombosis, pulmonary embolism, and
postoperative pneumonia

Pelvic problems - Stress incontinence

Cutaneous - Intertrigo (bacterial and/or fungal),

acanthosis nigricans, hirsutism, increased risk for
cellulites and carbuncles

Extremities - Venous varicosities, lower extremity

venous and/or lymphatic edema

Miscellaneous - Reduced mobility, difficulty

maintaining personal hygiene

Physical:

In the clinical examination, include measurement of the

anthropometric parameters and the standard detailed

examination required for the evaluation of persons with any

chronic multisystemic disorder such as obesity.

In the skin examination, include a search for hirsutism in

women, intertriginous rashes, acanthosis nigricans, and
possible contact dermatoses.

A detailed cardiac and respiratory evaluation is crucial to

exclude cardiomegaly and respiratory insufficiency.

In the abdominal examination, include an attempt at

excluding tender hepatomegaly (which may suggest NASH)
and distinguishing the striae distensae from the pink and
broad striae that would suggest cortisol excess.

When examining the extremities, include a search for joint

deformities such as coxa vara, evidence of osteoarthrosis, and
any pressure ulcerations.

Causes: The etiology of obesity is multifactorial. Among the facets

to be considered in the development of obesity are the following:

Metabolic factors

Genetic factors

Level of activity

Behavior

Endocrine factors

Race, sex, and age factors

Ethnic and cultural factors

Socioeconomic status

Dietary habits

Smoking cessation

Pregnancy and menopause

Psychologic factors

History of gestational diabetes

Lactational history in mothers

Secondary causes of obesity may include the following (also

see Image 2):
o

Hypothyroidism

Cushing syndrome

Insulinoma

Hypothalamic obesity

Polycystic ovarian syndrome

Genetic syndromes (eg, Prader-Willi syndrome,

Alstrm syndrome, Bardet-Biedl syndrome, Cohen
syndrome, Brjeson-Forssman-Lehmann syndrome,
Frhlich syndrome)

Growth hormone deficiency

Oral contraceptive use

Medication-related (eg, phenothiazines, sodium

valproate, carbamazepine, tricyclic antidepressants,
lithium, glucocorticoids, megestrol acetate,
thiazolidine diones, sulphonylureas, insulin,
andrenergic antagonists, serotonin antagonists
[especially cyproheptadine])

Eating disorders (especially binge-eating disorder,

bulimia nervosa, night-eating disorder)

Hypogonadism

Pseudohypoparathyroidism

Obesity related to tube feeding

DIFFERENTIALS

Section 4 of 11

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Acromegaly
Apnea, Sleep

Bulimia
Cardiac Cirrhosis
Cardiomyopathy, Dilated
Cardiomyopathy, Hypertrophic
Cholecystitis
Cholelithiasis
Cirrhosis
Cushing Syndrome
Depression
Diabetes Mellitus, Type 1
Diabetes Mellitus, Type 2
Fatty Liver
Growth Hormone Deficiency
Hiatal Hernia
Hirsutism
Hypercholesterolemia, Polygenic
Hypertension
Hypothyroidism
Insulinoma
Kallmann Syndrome and Idiopathic Hypogonadotropic
Hypogonadism
Lipodystrophy, Acquired Partial
Lipodystrophy, Generalized
Nephrotic Syndrome
Ovarian Polycystic Disease
Pseudo-Cushing Syndrome