Obesity, a common problem of increasing prevalence, is defined as a body mass index (BMI) ≥ 30 kg/m2, whereas overweight is a BMI of 25–29.9 kg/m2. It results from excessive calorie consumption relative to energy consumption (metabolic rate plus physical activity). Obesity increases the risk of diabetes mellitus, hyperlipidemia, and hypertension, thereby increasing the risk for atherosclerosis. It also predisposes to sleep apnea, gastroesophageal reflux disease (GERD), infertility, and degenerative arthritis of the spine and weight-bearing joints. Patients who are obese are also at increased risk for cancers of the breast, prostate, colon, and endometrium.
Genetics is the most important determinant for obesity. In a given environment, up to 80% of human obesity is due to genetic factors. Several novel hormones appear to act upon brain receptors to regulate appetite and metabolism, thereby determining an individual's predisposition to obesity.
Leptin is a hormone secreted by subcutaneous adipose tissue in response to fat storage or overfeeding. Leptin binds to brain α-melanocortin receptors and influences the secretion of neuropeptides, inhibiting neuropeptide Y and agouti-related peptide. It thereby promotes satiety and increases the body's metabolic rate. Leptin is also required for gonadotropin secretion. During starvation, reduced leptin secretion results in a lower metabolic rate and a reduction in gonadotropin secretion. Congenital leptin deficiency accounts for 1–2% of early-onset morbid obesity. Therapy with leptin, administered subcutaneously twice daily to leptin-deficient patients, dramatically reverses their morbid obesity, diabetes mellitus, hypertriglyceridemia, and hypogonadism.
Adiponectin is a protein hormone that is secreted by fat cells; in the circulation, adiponectin molecules aggregate to form larger hormonally active “multimers.” It stimulates muscles to increase glucose utilization while inhibiting hepatic glucose secretion. Adiponectin thereby increases insulin sensitivity. Ironically, obesity causes lower serum adiponectin levels, leading to insulin resistance and the metabolic syndrome. Adiponectin gene polymorphisms can impair adiponectin secretion or multimer formation, thereby causing insulin resistance and a predisposition to type 2 diabetes mellitus. Serum adiponectin levels are increased by weight loss, renal failure, and thiazolidinedione therapy.
Ghrelin is a 28-amino acid hormone that is secreted by the empty stomach; it acts upon the hypothalamus to stimulate appetite. Ghrelin levels tend to be low in obese individuals and high in adolescents. Patients who have gastric bypass procedures for obesity have markedly suppressed serum ghrelin levels.
α-Melanocyte-stimulating hormone (α-MSH) is a neuropeptide that regulates the hypothalamic control of food intake. Defects in the α-MSH (melanocortin 4) receptor are present in up to 5% of morbidly obese patients.
Familial partial lipodystrophy (Dunnigan–Kobberling syndrome) is an autosomal dominant disorder caused by missense mutations in the lamin A/C gene. Beginning at puberty, affected patients develop atrophy of subcutaneous fat in the extremities but obese proximal thighs, trunk, and face (type I) or absence of subcutaneous fat everywhere but in the face, which is very fat (type II). Patients may have muscle hypertrophy. Affected patients, especially women, are at risk for metabolic complications associated with insulin resistance, including glucose intolerance, diabetes mellitus, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and atherosclerosis.
Obesity is associated with mental retardation in several genetic syndromes expressing multiple congenital anomalies: eg, Prader–Willi syndrome (hypotonia, hypogonadism), Laurence–Moon–Bardet–Biedl syndrome (polydactyly, renal anomalies, retinitis pigmentosa, hypogonadism), Cohen's syndrome (microcephaly, hypotonia, short stature, ocular anomalies, neutropenia), and Biemond syndrome (diabetes mellitus, polydactyly, coloboma, facial anomalies, hypogonadism).
Several endocrine disorders do cause obesity. Cushing's syndrome causes central obesity (due to intraperitoneal fat) with relatively thin extremities; such patients usually have plethoric, rounded (moon) facies along with prominent supraclavicular and dorsocervical fat pads (buffalo humps). Alcoholism causes hypercortisolism and a similar syndrome. Hypothyroidism occasionally causes mild weight gain due to edema and fat accumulation. Hyperthyroidism may cause mild weight gain due to hyperphagia. Pancreatic insulinomas secrete excessive amounts of insulin, causing hypoglycemia and compensatory overeating. Growth hormone deficiency usually causes obesity in both children and adults.
Menopause is associated with a decrease in the resting metabolic rate, which increases body weight. Weight gain is greatest in the perimenopausal period. Hormone replacement therapy causes negligible weight gain. Obesity may be associated with other disorders as part of several recognized syndromes. Syndrome X (the cluster of obesity, diabetes, and hypertension) has a 50% hereditary component. Polycystic ovary syndrome refers to the combination of obesity with anovulation, amenorrhea, cystic ovaries, and hirsutism. Hypothalamic lesions can cause massive obesity and are often associated with headache, lethargy, depression, diabetes insipidus, and hypopituitarism.
- Aitman TJ: Genetic medicine and obesity. N Engl J Med 2003; 348:2138.
- Arterburn DE et al: The efficacy and safety of sibutramine for weight loss: a systematic review. Arch Intern Med 2004; 164:994. - Buchwald H et al: Bariatric surgery: a systematic review and metaanalysis. JAMA 2004;292:1724. - O'Meara S et al: A systematic review of the clinical effectiveness of orlistat used for the management of obesity. Obes Rev 2004;5:51. - Stern L et al: The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial. Ann Intern Med 2004;140:778.