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Increased WC has been shown to predict obesity-related diseases such as diabetes,

hypertension, dyslipidemia, and cardiovascular disease.

10–12 The waist-to-hip ratio

(WHtR) also provides an assessment of regional fat distribution. A waist-to-hip ratio

>1 in men and >0.8 in women indicates high intra-abdominal fat. Some research

suggests that WHtR is superior to both WC and BMI in determining obesity-related

cardiometabolic risk. Independent of BMI classification, higher waist circumference

is correlated with increased mortality.

13 Therefore, measurement of WC and the

WHtR are useful in identifying individuals that are normal weight or overweight with

health risk due to increased abdominal fat accumulation.

Table 36-1

BMI and Guidelines for Weight Classes

Weight Status BMI

a Obesity Class

Underweight <18.5

Normal ≥18.5–25

Overweight ≥25–30

Obesity ≥30–35 I

≥35–40 II

Extreme or severe obesity ≥40 III

aMetric conversion formula using kilograms and meters: BMI = Weight in kg/height in m

2

. Nonmetric conversion

formula using pounds and inches: BMI = weight in lb/height in inches

2 × 703.

BMI, body mass index.

Source: Jensen, Michael D et al. 2013 AHA/ACC/TOS guideline for the management

of overweight and obesity in adults: a report of the American College of

Cardiology/American Heart Association Task Force on Practice Guidelines and The

Obesity Society. J Am Coll Cardiol. 2014;63:2985–3023.

EPIDEMIOLOGY

Obesity is a major public health concern worldwide and is a leading cause of

numerous medical conditions (e.g., cardiovascular disease, hypertension,

dyslipidemia, diabetes, sleep apnea) and premature death

10,13

(Table 36-2).

According to the WHO, there were approximately 1.9 billion overweight and 600

million obese adults globally in 2014.

1

In the United States, the prevalence of obesity

has been examined as part of the National Health and Nutrition Examination Survey

(NHANES). The NHANES data from 2011 to 2012 showed that 68.5% of US adults

were overweight or obese and 34.9% were obese and 6.4% were extremely obese.

3

Adult obesity usually results from a steady weight gain from the mid-20s to between

ages 40 and 59, when the prevalence of obesity peaks.

3 Severe obesity is more

common in women.

3 The most recent NHANES data report overweight, obesity, and

extreme obesity were more prevalent among non-Hispanic black women.

3 Despite

the striking increases in obesity prevalence in the 1980s and 1990s, current

NHANES data suggest that the prevalence of obesity may be stabilizing, showing

nonsignificant increases compared with the 2003 to 2004 NHANES data.

3

Table 36-2

Obesity-Related Health Conditions

Cardiovascular Dermatologic

Hypertension Striae distensae (stretch marks)

Heart failure Skin tags

Coronary artery disease Acanthosis nigricans

Stroke Intertrigo

Pulmonary Gastrointestinal

Obstructive sleep apnea Gallstones

Asthma Gastroesophageal reflux disease (GERD)

Metabolic Psychological

Dyslipidemias Eating disorders

Diabetes mellitus Depression

Hyperinsulinemia Socialstigma

Cancer Gynecologic and Obstetric Complications

Esophageal Gestational diabetes

Colon Preeclampsia

Liver Infertility

Prostate Musculoskeletal

Uterine Osteoarthritis

Breast Other

Ovarian Nonalcoholic fatty liver disease (NAFLD)

Gallbladder Impotence

Kidney

Cervix

Sources: Hildago LG. Dermatologic complications of obesity. Am J Clin Dermatol. 2002;3:497–506; Malnick SD,

Knobler H. The medical complications of obesity. Q J Med. 2006;99:565–579.

p. 757

p. 758

Obesity is also a significant problem among children and adolescents, with

alarmingly high prevalence rates. Overweight and obesity in children and

adolescents (age 2–19 years) are based on the Centers for Disease Control (CDC)

growth charts; overweight is defined as BMI in the 85th to 95th percentile and obese

is defined as BMI greater than the 95th percentile.

7 The WHO estimates that greater

than 42 million children under age 5 are overweight.

1 NHANES data from 2011 to

2012 reported that 31.8% of children and adolescents (age 2–19 years) were either

overweight or obese and 16.9% were obese.

3 Non-Hispanic white youth show lower

prevalence of obesity as compared to non-Hispanic black and Hispanic youth. As

with adults, the prevalence has stabilized, with no significant change compared with

the 1999 to 2000 NHANES data.

3 However, because this prevalence rate has

remained alarmingly high, childhood obesity must be addressed because of the health

consequences the obese child takes on into adulthood. Childhood and adolescent

obesity shows an increased risk for adult overweight and obesity.

14 Also, studies

have shown that overweight and obesity in childhood and adolescence are correlated

with an increased risk of adult diabetes, hypertension, ischemic heart disease and

stroke physical morbidity, and premature mortality.

15

ETIOLOGY AND PATHOPHYSIOLOGY

Simply stated, obesity results from an imbalance of energy intake and energy

expenditure. Body fat accumulation will occur when an individual consumes more

calories than are burned. However, the exact cause of obesity is difficult to identify

and is likely a mixture of genetic, environmental, behavioral, and neurohormonal

factors. Investigators have tried to understand the origin of this disease by studying

the influences of society, culture, socioeconomic status, medical conditions,

medications that stimulate appetite, parental weight, and hereditary traits on dietary

habits and physical activity.

16 Each potential cause of obesity continues to be

investigated as a possible target for treatment and prevention of this chronic disease.

There have been several association studies linking short sleep duration and

metabolic changes such as obesity, insulin resistance, and diabetes.

17,18 One study

showed that children aged 30 months and younger who lacked sleep were at risk of

exhibiting obesity at 7 years.

19 Another trial in adults found that sleep duration was

negatively correlated with BMI.

20 Alteration of the hypothalamic regulation of

appetite and energy expenditure owing to sleep loss is one possible explanation.

Normally, when a person has eaten an adequate amount of food, neurotransmitters or

peptides in the brain signal the satiety centers in the hypothalamus and there is a

reduced desire to eat. Sleep loss has also been shown to be associated with low

leptin levels and high ghrelin levels; both factors contribute to signaling of energy

deficit and hunger, which may contribute to overeating and obesity.

21

Recently, research has begun to investigate the role of that gut microbiota in body

composition. Data suggest that interventions that negatively impact the biodiversity of

the gut microbiota such as Cesarean delivery (vs. vaginal delivery), maternal

prepregnancy BMI, and early antibiotic use may increase the risk of obesity.

22 A

large cohort trial found that the repeated use of broad-spectrum antibiotics during the

first 2 years of life has been associated with early childhood obesity.

23

Genetic Features

There is a clear link between genetics and obesity, both in childhood and adulthood,

shown mostly through twin and adoption studies.

24–29 One study by Wardle et al.

26

demonstrated a heritability estimate of 77% for BMI and 76% for waist

circumference. Genetic studies have identified genes that may be associated with

weight.

24,30 There is also evidence that body fat distribution is controlled by genetic

factors with waist-to-hip ratio showing heritability of up to 60%.

31

HYPOTHALAMUS DYSREGULATION

The hypothalamus plays a key role in body weight regulation by controlling satiety

(the feeling of fullness), hunger, and in turn food intake. Neurobiologic theories of

eating disorders have focused on dysregulation of the hypothalamic–pituitary–

adrenal, hypothalamic–pituitary–gonadal, and hypothalamic–pituitary–thyroid axes as

well as dysregulation of neurotransmitters, neuropeptides, endogenous opioids,

growth hormone, insulin, and leptin.

32 Alterations in hypothalamic functioning are

associated with appetite changes, mood disorders, and neuroendocrine

disturbances.

33 The hypothalamus is the major appetite and eating control center in

the brain and is sensitive to a variety of facilitatory and inhibitory neurotransmitters

and polypeptide neurohormones from the brain and gastrointestinal (GI) tract. The

hypothalamus receives input from peripheral satiety sites (e.g., gastric and pancreatic

peptides released secondary to food passing through the GI tract), from leptin that is

produced by fat cells, and from the catecholamine neurotransmitter system in the

brain.

33,34

NEUROTRANSMITTER DYSREGULATION

Serotonin

Serotonin plays an important role in postprandial satiety, anxiety, sleep, mood,

obsessive–compulsive, and impulse control disorders. Serotonin has an inhibitory

effect on appetite and is responsible for satiety or the feeling of fullness after food

intake.

35,36 Diminished serotonin activity can contribute to increased food intake and

carbohydrate craving.

35 The reduction in serotonin activity may upregulate the

appetite or satiety centers in the brain, thereby increasing the amount of food a person

wants to eat. Agents that block postsynaptic serotonin activity (e.g., clozapine,

mirtazapine, and atypical antipsychotics) can stimulate appetite and may cause

weight gain.

Dopamine

Agents that increase dopamine activity (e.g., apomorphine, a dopamine agonist;

levodopa, a metabolic precursor of dopamine; and amphetamine, a stimulator of

release of dopamine from presynaptic stores) have been shown to have anorexic

effects.

37 Dopamine agonists increase dopaminergic transmission and motor activity,

which causes loss of appetite and hyperactivity. The central nervous system (CNS)

effects of dopaminergic agents occur in the cerebral cortex, in the reticular activating

system, and in the hypothalamic feeding center. The mesolimbic–mesocortical

dopaminergic circuits are important for behavior reward and reinforcement, and are

involved with “addictive” behaviors.

37 Dopamine-augmenting agents such as

amphetamines were once used for the treatment

p. 758

p. 759

of exogenous obesity and produced tolerance, dependence, and withdrawal reactions.

Conversely, dopamine receptor antagonists such as chlorpromazine and clozapine

may cause dysphoria and are often associated with weight gain.

Norepinephrine

The hypothalamus is innervated by noradrenergic pathways; thus, norepinephrine is

involved in the regulation of eating behavior, the hypothalamic control of thyrotropinreleasing hormone secretion, corticotropin-releasing hormone (CRH) release, and

gonadotropin secretion.

37 D-Amphetamine, which inhibits the reuptake of

norepinephrine, decreases hunger sensations and food intake. Abnormalities in leptin

and β3

-adrenergic activity have been associated with obesity and diabetes.

38 The β3

-

adrenoceptor is involved in a feedback loop with leptin to regulate energy balance,

lipolysis in adipocytes, serum insulin levels, and food intake.

39 People with

hereditary obesity or type 2 diabetes mellitus may have abnormalities in the β3

-

adrenoceptor or in leptin activity, signaling, or receptors.

38 A genetic variant of the

β3

-adrenoceptor in humans has been associated with severe obesity and type 2

diabetes. It is possible that some cases of obesity may be secondary to failure of the

β3

-adrenoreceptor on brown adipocytes to respond appropriately to leptin-induced

sympathetic activity. β3

-Adrenergic receptor agonists are being studied to induce

thermogenic activity and promote weight loss when combined with a calorierestricted diet.

39

NEUROPEPTIDE AND LEPTIN DYSREGULATION

Leptin

Leptin is a protein synthesized by adipocytes, gastric chief cells, skeletal muscle, and

other organs. It acts on receptors of the hypothalamus to act as an afferent satiety

signal in the brain to regulate body fat mass.

33,40,41 Leptin reduces food intake,

decreases serum glucose and insulin levels, increases metabolic rate, and reduces

body fat mass and weight by reducing neuropeptide Y (NPY) activity (a potent

feeding stimulant secreted by the hypothalamus and cells in the gut).

40,42 Leptin serum

levels are highly correlated with BMI and body fat and its secretion has a circadian

rhythm and an oscillatory pattern similar to other hormones.

38,41,43

Leptin is supposed to signal the brain to reduce the desire to eat, but this does not

occur in patients with obesity.

40

It has been postulated that some individuals with

obesity may have partially resistant hypothalamic receptors or that there is a defect in

the blood–brain barrier transport system for bringing leptin into the brain.

33,40,43,44

Cerebrospinal fluid leptin levels in some patients with obesity have been found to be

much lower than expected compared with serum leptin levels, which suggests that the

uptake of leptin into the brain may be defective.

33 Other studies suggest that obese

individuals may have a dysregulation of leptin in response to overfeeding, with a

lack of serum increase. Compared with lean individuals, this may indicate that the

patients with obesity lack a protective mechanism of increase in serum leptin levels

in response to increased caloric intake to prevent weight gain.

45

It has been

demonstrated that elevated baseline serum leptin levels are associated with inability

to maintain weight loss.

46 Another potential mechanism may be reduced leptin

receptor protein expression found in skeletal muscle of patients with obesity that

could lead to leptin resistance in the presence of elevated leptin serum levels.

47

Leptin and leptin-like products have been investigated for promotion of weight loss,

but leptin resistance impedes its clinical utility.

40,48

Neuropeptides and Neurohormones

Appetite is regulated in part via orexigenic neuropeptides which signal hunger and

anorexigenic neuropeptides which signal satiety within the hypothalmus.

Neuropeptide Y (NPY) and agouti-related peptide (AgRP) are found in the central

nervous system and are potent stimulators of appetite.

49,50 POMC (proopiomelanocortin) is a precursor protein to α-melanocyte-stimulating hormone (αMSH) and binds to melanocortin-3 receptors (MC3R) and melanocortin-4 receptors

(MC4R) to suppress food intake.

34,49 Research on MC4R analogs is ongoing, but

trials with selective MC3R agonist failed to suppress feeding.

34,49

Several other neurohormonal signals and peptides play a role in appetite

regulation. Ghrelin is a hormone that is released from the stomach before meals and

acts to increase appetite via stimulation of NPY and AgRP.

49 There is a negative

correlation between ghrelin levels and BMI where patients with obesity have

increased ghrelin and levels remain elevated even after weight loss.

49 Peptide

tyrosine tyrosine (peptide YY or PYY) and pancreatic polypeptide (PP) are

pancreatic are chemically related to NPY but work as appetite suppressants.

49,50

Early studies of experimental PYY administration have found an intranasal

formulation to be ineffective for weight reduction and poorly tolerated in obese

patients.

51 A small dose escalation study of subcutaneous injections of two forms of

PYY, PYY1–36

, and PYY3–36

, found some positive results on inducing lower

subjective hunger and thirst ratings and higher satiety ratings with PPY3–36

administration.

52 Amylin is a pancreatic hormone that is released in response to

eating and functions as an anorectic hormone.

49 Administration of amylin has been

shown to result in reduced food intake and weight loss.

53 Glucagon-like peptide-1

(GLP-1) is secreted from the gut in response to food intake and works to reduce food

intake, suppress glucagon secretion, and delay gastric emptying.

49 Cholecystokinin

(CCK) is a hormone that is released from the small intestines in response to food

intake and works to suppress further food intake.

49

Environmental Influences and Behavioral Factors

Despite the known genetic influences predisposing certain individuals to obesity,

environmental influences play a role by providing exposure to a lifestyle promoting

energy imbalance and may influence epigenetic factors. Modern society provides an

overabundance of inexpensive, readily accessible calorie-dense food. Decreased

energy expenditure due to a sedentary lifestyle has become common, further

exacerbating an obesogenic lifestyle. A review of twin and adoption studies by

Silventoinen et al.

25 clearly demonstrated that environmental factors affect BMI

variation in childhood, but the effect of common environment disappears in

adolescence. These results portray a stronger influence of genetics in the incidence of

obesity in adulthood.

Medical Conditions and Medications

Although less common, certain medical conditions may cause overweight and

obesity.

6 Genetic syndromes may be the primary cause of obesity such as Prader–

Willi, Bardet–Biedl, Cohen, Alström, and Froehlich syndromes. Other primary

causes of obesity include monogenic disorders such as melanocortin-4 receptor

mutation, leptin deficiency, and POMC deficiency. Secondary causes of obesity

include neurologic issues such as brain injury, brain tumors, and hypothalamic injury.

Endocrine disorders may also be a secondary cause of overweight and obesity such

as polycystic ovarian syndrome, Cushing syndrome, and growth hormone deficiency.

Hypothyroidism is often cited as a secondary cause of obesity because elevated TSH

is correlated with obesity.

54 But the relationship between hypothyroidism and obesity

is complex; because leptin and melanocortin influence the release of TSH, causality

has yet to be established.

54–56 Psychological causes of obesity include eating

disorders and depression when associated with overeating or binging. Several

medications are associated with weight gain. These include antipsychotics, steroids,

insulin, sulfonylureas, thiazolidinediones, some antidepressants, and some

anticonvulsants.

57 When treating overweight and obesity, if medications associated

with weight gain are identified, substitution with possible alternatives should be

attempted. Table 36-3 provides a list of medications that may cause weight gain

along with potential alternatives.

p. 759

p. 760

Table 36-3

Common Drugs and Their Effect on Weight

Associated with Weight

Loss

Associated with

Minimal Weight Gain

or Weight Neutral

Associated with Weight

Gain

Antidepressants Bupropion Fluoxetine, imipramine TCAs, MAOIs,

paroxetine, fluvoxamine,

venlafaxine, duloxetine,

mirtazapine

Antipsychotics Aripiprazole, quetiapine,

ziprasidone

Clozapine, olanzapine,

risperidone

Neurologic Topiramate, zonisamide,

felbamate

Lamotrigine Valproic acid, gabapentin,

pregabalin,

carbamazepine, vigabatrin,

lithium

Glucose-lowering GLP-1 agonists,

metformin, pramlintide,

SGLT-2 inhibitors

DPP-4 inhibitors, αglucosidase inhibitors

Insulin, sulfonylureas

(especially glyburide),

meglitinides,

thiazolidinediones

Antihypertensives ACEIs, ARBs, CCBs,

doxazosin

β-adrenergic blockers,

(especially propranolol), αadrenergic blockers

(prazosin, terazosin)

Contraceptives Barrier methods, Oral

contraceptives

Injectables (especially

medroxyprogesterone)

Antihistamines Second generation First generation

Anti-inflammatory NSAIDs, DMARDs Corticosteroids

ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker;

DMARD, disease-modifying antirheumatic drug; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1;

MAOI, monoamine oxidase inhibitor; NSAID, nonsteroidal anti-inflammatory drug; SGLT-2, sodium-glucose-linked

transporter-2; TCA, tricyclic antidepressant.

CLINICAL FEATURES

CASE 36-1

QUESTION 1: S.B. is a 48-year-old woman with a past medical history of hypertension, sleep apnea,

osteoarthritis, and depression. She states that she has been overweight since she was a toddler. She reports

having tried multiple diets during the past 30 years, but has had little success with weight loss and always

regains any weight she manages to lose. Her height is 168 cm, current weight is 91 kg, and WC is 96 cm. She

presents to her primary physician for a routine physical examination. She complains of dissatisfaction with her

weight. She reports having tried multiple diets during the past 20 years, but has had little success with weight

loss and always regains any weight she manages to lose. S.B. expresses a desire to attempt medication therapy

for weight loss. Her current medications include hydrochlorothiazide, metoprolol, naproxen, and paroxetine. Her

blood pressure is currently 162/98 mm Hg and she is complaining of daytime fatigue due to sleep apnea. How is

obesity defined and assessed in a patient like S.B.?

Initial Assessment

Current guidelines suggest that weight status should be assessed in all patients.

6,7