Neuroendocrine Targets for the Treatment of Obesity: Physiological Roles and Unrealized Opportunities

J.   A.   Harrold; G.      Williams; S.      Wong

Abstract

In recent years, knowledge has advanced rapidly about the signals which indicate the bodys energy requirements and the neuronal circuits that can sense and respond appropriately to these signals, by effecting changes in food intake and energy expenditure. Much interest has focused on the circulating hormones leptin and insulin. Leptin is expressed predominantly in white adipose tissue and its circulating levels are broadly proportional to fat mass (the bodys major energy store). Insulin also circulates at levels that reflect adiposity. Both hormones can signal fat mass to the brain: they readily enter the hypothalamus and other brain regions, where they target specific neuronal populations with the overall effect of inhibiting feeding and increasing energy expenditure. Key hypothalamic targets for both leptin and insulin include neurons expressing the orexigenic (appetite-stimulating) peptide neuropeptide Y (NPY), which are inhibited by both hormones. The gut also generates nutritional signals that reach the brain. These include cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and the recently identified PYY(3-36), all peptides released from the gut after feeding and which act both centrally (and peripherally in the case of CCK and GLP-1) to inhibit hunger. By contrast, ghrelin is expressed mainly in the stomach and its circulating concentrations rise during fasting; - it acts to stimulate food intake, in part via stimulation of the hypothalamic NPY neurons. These and other signals, describing different aspects of energy balance, converge upon and are integrated by specific neuronal populations in the hypothalamus. Mutations in key components of these circuits underlie some syndromes of genetic obesity in rodents, but are responsible for only a small minority of human obesity - which is mostly due to adverse lifestyle. Various abnormalities of leptin, insulin and hypothalamic peptides have been identified in dietaryinduced obesity in rodents, which is more closely analagous to ‘common” human obesity. The relevance of many of these various players to human energy homeostasis remains uncertain, but some promising novel anti-obesity drugs; are likely to emerge in the next few years.

Keywords: leptin, insulin, ghrelin, hypothalamus