Increased WC has been shown to predict obesity-related diseases such as diabetes,
hypertension, dyslipidemia, and cardiovascular disease.
(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.
BMI and Guidelines for Weight Classes
Extreme or severe obesity ≥40 III
aMetric conversion formula using kilograms and meters: BMI = Weight in kg/height in m
formula using pounds and inches: BMI = weight in lb/height in inches
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.
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
According to the WHO, there were approximately 1.9 billion overweight and 600
million obese adults globally in 2014.
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.
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 The most recent NHANES data report overweight, obesity, and
extreme obesity were more prevalent among non-Hispanic black women.
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.
Obesity-Related Health Conditions
Hypertension Striae distensae (stretch marks)
Coronary artery disease Acanthosis nigricans
Obstructive sleep apnea Gallstones
Asthma Gastroesophageal reflux disease (GERD)
Dyslipidemias Eating disorders
Cancer Gynecologic and Obstetric Complications
Esophageal Gestational diabetes
Ovarian Nonalcoholic fatty liver disease (NAFLD)
Knobler H. The medical complications of obesity. Q J Med. 2006;99:565–579.
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.
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
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.
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.
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
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.
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.
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.
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.
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.
demonstrated a heritability estimate of 77% for BMI and 76% for waist
circumference. Genetic studies have identified genes that may be associated with
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%.
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
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
NEUROTRANSMITTER DYSREGULATION
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
35,36 Diminished serotonin activity can contribute to increased food intake and
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
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
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
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.
The hypothalamus is innervated by noradrenergic pathways; thus, norepinephrine is
37 D-Amphetamine, which inhibits the reuptake of
norepinephrine, decreases hunger sensations and food intake. Abnormalities in leptin
-adrenergic activity have been associated with obesity and diabetes.
adrenoceptor is involved in a feedback loop with leptin to regulate energy balance,
lipolysis in adipocytes, serum insulin levels, and food intake.
hereditary obesity or type 2 diabetes mellitus may have abnormalities in the β3
adrenoceptor or in leptin activity, signaling, or receptors.
-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
-adrenoreceptor on brown adipocytes to respond appropriately to leptin-induced
-Adrenergic receptor agonists are being studied to induce
thermogenic activity and promote weight loss when combined with a calorierestricted diet.
NEUROPEPTIDE AND LEPTIN DYSREGULATION
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).
levels are highly correlated with BMI and body fat and its secretion has a circadian
rhythm and an oscillatory pattern similar to other hormones.
Leptin is supposed to signal the brain to reduce the desire to eat, but this does not
occur in patients with obesity.
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.
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.
demonstrated that elevated baseline serum leptin levels are associated with inability
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.
Leptin and leptin-like products have been investigated for promotion of weight loss,
but leptin resistance impedes its clinical utility.
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.
(MC4R) to suppress food intake.
34,49 Research on MC4R analogs is ongoing, but
trials with selective MC3R agonist failed to suppress feeding.
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.
correlation between ghrelin levels and BMI where patients with obesity have
increased ghrelin and levels remain elevated even after weight loss.
tyrosine tyrosine (peptide YY or PYY) and pancreatic polypeptide (PP) are
pancreatic are chemically related to NPY but work as appetite suppressants.
Early studies of experimental PYY administration have found an intranasal
formulation to be ineffective for weight reduction and poorly tolerated in obese
51 A small dose escalation study of subcutaneous injections of two forms of
, found some positive results on inducing lower
subjective hunger and thirst ratings and higher satiety ratings with PPY3–36
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.
(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.
(CCK) is a hormone that is released from the small intestines in response to food
intake and works to suppress further food intake.
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
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
Medical Conditions and Medications
Although less common, certain medical conditions may cause overweight and
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
54 But the relationship between hypothyroidism and obesity
is complex; because leptin and melanocortin influence the release of TSH, causality
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
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.
Common Drugs and Their Effect on Weight
Antidepressants Bupropion Fluoxetine, imipramine TCAs, MAOIs,
Antipsychotics Aripiprazole, quetiapine,
Neurologic Topiramate, zonisamide,
Lamotrigine Valproic acid, gabapentin,
Glucose-lowering GLP-1 agonists,
DPP-4 inhibitors, αglucosidase inhibitors
Antihypertensives ACEIs, ARBs, CCBs,
(especially propranolol), αadrenergic blockers
Contraceptives Barrier methods, Oral
Antihistamines Second generation First generation
Anti-inflammatory NSAIDs, DMARDs Corticosteroids
transporter-2; TCA, tricyclic antidepressant.
QUESTION 1: S.B. is a 48-year-old woman with a past medical history of hypertension, sleep apnea,
obesity defined and assessed in a patient like S.B.?
Current guidelines suggest that weight status should be assessed in all patients.
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