Abnormalities of Hormones and Other Circulating Factors

Growth hormone Obesity is typically accompanied by a decrease in growth hormone (GH) levels and an increase in growth hormone binding protein levels. An inverse relation exists between GH levels and percentage fat mass. GH levels fall with increasing age. GH is released by the anterior pituitary and affects lipid, carbohydrate, and protein metabolism. GH also controls the rate of skeletal and visceral growth. GH is lipolytic in adipose tissue. Animal studies show enhanced catecholamine-induced lipo-lysis and increased /3-adrenoreceptors in adipocytes of GH treated animals. The rises in GH after meals, with sleep, and in response to secretogogues such as arginine or levodopa are blunted in obese people. GH stimulates secretion of insulin-like growth factor-1 (IGF-1). However, IGF-1 is increased in obesity, suggesting a difference in sensitivity to GH. The defects in GH and IGF-1 are reversed by weight reduction.

The hypothalamic-pituitary-adrenal axis The hypothalamic-pituitary-adrenal (HPA) axis may be abnormal in obesity. Patients with Cushing's syndrome display a number of clinical features that resemble those seen in patients with the metabolic syndrome, including abdominal obesity, insulin resistance, impaired glucose homeostasis, hypertension, and lipid abnormalities. These similarities led to the hypothesis that a dysregulation of the HPA axis in the form of functional hypercortisolism could potentially be a cause for abdominal obesity and its different metabolic consequences. High levels of emotional or physical stress are thought to increase cortisol secretion or turnover and thereby increase visceral obesity.

Another potential mechanism involves the peripheral metabolism of cortisol. The enzyme 11-^-hydroxysteroid dehydrogenase, which converts steroid precursors to cortisol, is expressed in adipose tissue. With increasing obesity, more cortisol is derived from cortisone in adipose tissue due to the increased activity of this hormone. Urine studies in obesity also show an increase in the ratio of tetra-hydrocortisol to tetrahydrocortisone, indicating a relative increase in the pathways leading to cortisol formation.

Cytokines Adipose tissue secretes a number of cytokines, such as TNF-a and interleukins, which may play a role in fat metabolism and insulin resistance. TNF-a has been shown to alter basal and glucose-stimulated insulin secretion and to produce insulin resistance in isolated cell lines. Adipocytes also produce IL-6, —10, and —11, which stimulate C-reactive protein, a systemic marker of inflammation. All of these ILs are increased in obesity. IL-6 and its subsequent inflammation have been postulated to play an etiologic role in the increased risk of thrombo-embolism observed in obese patients. Adipose tissue is also capable of producing plasminogen activator inhibitor-1, which may play a role in the increased risk of thromboembolism. Plasma IL-8 is increased in normoglycemic obese subjects and is related to fat mass and to TNF-a levels. Circulating IL-8 is also acutely upregulated by hyperinsulinemia. An increase in circulating IL-8 may be one of the factors linking obesity with greater cardiovascular risk.

Renin-angiotensin system Several components of the renin-angiotensin system are expressed by the adipose tissue. Angiotensinogen levels are increased and have been linked to hypertension and increased cardiovascular risk in obesity.

Leptin Leptin, the product of the ob gene, is made predominantly in adipose tissue. Leptin receptors are present in the hypothalamus. Leptin was postulated to act as a signal from adipose tissue to the brain to regulate fat stores. However, serum leptin levels correlate positively with body fat stores and are higher in obese people. Females have higher serum leptin levels than males, but this association does not appear to be due to estrogen levels. Leptin is found in greater concentrations in abdominal subcutaneous fat compared to visceral fat. The mechanisms for these differences are not known, but it is possible that this may play some role in the differential metabolic responses of subcutaneous and visceral fat.

Ghrelin Ghrelin is a potent growth hormone secre-tagogue that is produced mainly by the stomach. Administration of ghrelin increases food intake, and ghrelin levels increase with dieting and weight loss. However, serum ghrelin has a negative correlation with percentage body fat, so levels in obese people are lower than in nonobese people.

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