Leptin and Obesity

Abstract

Leptin burst onto the scene in 1994 and transformed research into obesity and energy balance. Immediately, hopes were raised that this peptide, secreted by adipose tissue, might be causally related to human obesity, and that the regulatory mechanisms underlying its action might be manipulated for therapeutic benefit. In the last 6 years, the concentrated effort of the research community, both academic and commercial, has made enormous strides towards understanding the full range of physiological effects of leptin. In the mouse, leptin deficiency (ob/ob) induces hyperphagia, massive obesity and diabetes. Administration of leptin protein reverses this phenotype and results in rapid bodyweight loss, mainly in the form of fat. Leptin also modestly reduces food intake and bodyweight in normal lean rodents on systemic administration. Leptin is much more potent when administered directly into the cerebroventricular system of the brain. This observation, and the identification of leptin receptor expression in hypothalamic nuclei with an established regulatory function in energy homeostasis, confirms the CNS as a primary site of action of leptin. A number of leptin-sensitive, receptor-expressing hypothalamic neurons of different neurochemical phenotype have been identified, and leptin receptor mRNA and protein are widespread elsewhere in the mammalian brain. Leptin provides two forms of feedback to regulatory systems in the brain, a dynamic reflection of diurnal feeding pattern (where it may interact with satiety signals), and a basal level of secretion encoding body fat storage (a plausible lipostat). The absence of leptin is a potent signal of starvation, and in this state reduced leptin feedback regulates the activity of compensatory neuropeptide systems in the hypothalamus to drive the voluntary hyperphagia displayed by rodents when released back to ad libitum feeding. Despite the initial excitement over the therapeutic potential of leptin, these expectations have now begun to wane. Assessments of the value of leptin, and of potential therapies based on its activities, are now more realistic and may involve targeting of specific subpopulations of individuals, or particular weight loss strategies. This review focuses deliberately upon the possible exploitation strategies that are still patent.