The hypothalamus and the regulation of energy homeostasis: lifting the lidon a black box

The hypothalamus is the focus of many peripheral signals and neural pathway s that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of 'feeding' and 'satiety' centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypo thalamic neurotransmitters and their potential as targets for the developme nt of new drugs to treat obesity and other nutritional disorders. Neuropept ide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (A RC) that project to important appetite-regulating nuclei, including the par aventricular nucleus (PVN). NPY injected into the PVN is the most potent ce ntral appetite stimulant known, and also inhibits thermogenesis; repeated a dministration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunge r in this and other conditions of energy deficit. They therefore act homeos tatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in whic h leptin inhibition is lost through mutations affecting leptin or its recep tor. Antagonists of the Y5 receptor (currently thought to be the NPY 'feedi ng' receptor) have anti-obesity effects. Melanocortin-4 receptors (MC4-R) a re expressed in various hypothalamic regions, including the ventromedial nu cleus and ARC. Activation of MC4-R by agonists such as a-melanocyte-stimula ting; hormone (a cleavage product of pro-opiomelanocortin which is expresse d in ARC neurones) inhibits feeding and causes weight loss. Conversely, MC4 -R antagonists such as 'agouti' protein and agouti gene-related peptide (AG RP) stimulate feeding and cause obesity. Ectopic expression of agouti in th e hypothalamus leads to obesity in the AW mouse, while AGRP is co-expressed by NPY neurones in the ARC. Synthetic MC4-R agonists may ultimately find u se as anti-obesity drugs in human subjects Orexins-A and -B, derived from p repro-orexin, are expressed in specific neurones of the lateral hypothalami c area (LHA). Orexin-A injected centrally stimulates eating and prepro-orex in mRNA is up regulated by fasting and hypoglycaemia. The LHA is important in receiving sensory signals from the gut and liver, and in sensing glucose , and orexin neurones may be involved in stimulating feeding in response to falls in plasma glucose.