CENTRAL-NERVOUS-SYSTEM AND BODY-WEIGHT REGULATION

The discovery of both neuropeptide Y and of leptin has led to a better understanding of the pathophysiology of obesity syndromes in animal m odels. It has strengthened the concept of the importance of the hypoth alamus in the etiology of these syndromes. Due to alterations in the r egulation of the hypothalamus, e.g. by insulin, by leptin or by decrea ses in the availability of glucose in specific brain areas, most anima l models of obesity have higher than normal hypothalamic neuropeptide Y levels. As neuropeptide Y is a potent orexigenic agent, this hypotha lamic defect explains why obese rodents are hyperphagic. Increased hyp othalamic neuropeptide Y levels produce hyperinsulinemia and hypercort icism, two abnormalities previously reported in obesity, but whose ori gin is now known to be driven by neuropeptide Y. As hyperinsulinemia f avors lipid accretion and muscle insulin resistance, and as hypercorti cism favors the occurrence of both high circulating triglyceride level s and muscle insulin resistance, it may be appreciated that most disor ders previously reported in obesity can now be explained by high hypot halamic neuropeptide Y levels. Leptin, produced and secreted by adipos e tissue, is a potent anorectic agent whose main action is exerted wit hin the hypothalamus in which it has been shown to decrease neuropepti de Y, therefore food intake. Leptin secretion is favored, in particula r, by insulin as well as by glucocorticoids. When leptin is administer ed to obese mice of the ob/ob strain (which do not produce nor secrete leptin due to a gene mutation), their food intake, body weight and mo st metabolic abnormalities are normalized. However, in the majority of genetically obese rodents, as well as in obese humans, circulating le vels of leptin are high. This is related to hyperinsulinemia - and hyp ercorticosteronemia - induced leptin oversecretion, as well as to cent ral leptin receptor dysfunctions preventing normal leptin access to an d action within specific brain areas. Under these conditions and to pr event the effects of elevated hypothalamic neuropeptide Y levels, neur opeptide Y antagonists or active leptin agonists must be found. Neurop eptide Y and leptin further underline the existence of functional rela tionship between the brain (hypothalamus) and the periphery (adipose t issue, muscle). Lack of leptin (mutated leptin gene) or inefficient le ptin action (leptin receptor defect) results in increased hypothalamic neuropeptide Y levels. The latter favor hyperinsulinemia and hypercor ticism both producing oversecretion of leptin which, when inefficient, cannot decrease neuropeptide Y: a vicious circle is created which mai ntains either a ''thrifty phenotype'' favoring fat depot or overt obes ity, depending on the degree of hyperphagia.