Leptin and the obesity hypoventilation syndrome: a leap of faith?

he discovery of the anti-obesity hormone leptin (the name is derived from the Greek " leptos " meaning " thin "), the product of the ob gene, 1 has fuelled a recent surge of interest in the mechanisms regulating mammalian fat stores. Leptin, a 16 kD protein of 167 amino acids with a similar crystal structure to cytokines, 2 is produced primarily by white adipose tissue. 3 The hormone elicits appetite suppression and weight loss. 4 5 Leptin circulates in the plasma in the free and protein bound forms. Circulating plasma leptin levels reflect the amount of energy storage in adipose tissue and increase exponentially with increasing fat mass. 6 Plasma leptin levels also respond to short term energy imbalance , increasing during periods of over-feeding and decreasing with fasting. 7 8 The hormone activates specific receptors 9 located at several sites throughout the brain, but plays a key role at the hypothalamus, in particular, where it alters the expression of several hypothalamic neuropeptides. 10 11 One of these, neuropeptide Y (NPY), is a potent stimulator of food intake and activator of the hypothalamic-pituitary-gonadal axis. Leptin inhibits synthesis of hypo-thalamic NPY and downregulation of NPY is associated with appetite suppression , increased sympathetic nervous system outflow, and increased energy expenditure. 12 Increasing leptin levels activate the thyroid hormone, gonadal, and growth hormone axes and suppress the pituitary-adrenal axis. 13 It must be emphasised that human obesity is a complex disorder, probably resulting from both multigenetic and environmental predispositions, and that leptin deficiency is a very rare cause of human obesity. 14 Indeed, circulating leptin levels are typically higher than normal in human obesity, indicating that it is a lep-tin resistant state. 15 Even within the hypothalamus the NPY axis is clearly not a final common pathway for appetite control as the appetite stimulating orex-ins can induce feeding despite blockade of the NPY axis. Leptin production is regulated by several factors. 17 18 Insulin and glucocorticoids act directly on adipocytes to increase leptin production, and chronic hyper-insulinaemia and increased cortisol turnover may underlie the increase in leptin expression observed in obesity. Similarly, the observed increase in serum leptin levels 4–7 hours after meals is probably related to increased circulating insulin in concert with the permissive effects of cortisol. Fasting results in decreased serum leptin levels—probably through falling insulin levels and the ability of catecholamines to decrease leptin expression (isoproterenol and β …