Leptin and obesity - The story so far and its therapeutic implications

Leptin burst onto the scene in 1994 and transformed research into obesity a nd energy balance. Immediately, hopes were raised that this peptide, secret ed by adipose tissue, might be causally related to human obesity, and that the regulatory mechanisms underlying its action might be manipulated for th erapeutic benefit. In the last 6 years, the concentrated effort of the research community, bot h academic and commercial, has made enormous strides towards understanding the full range of physiological effects of leptin. In the mouse, leptin def iciency (ob/ob) induces hyperphagia, massive obesity and diabetes. Administ ration of leptin protein reverses this phenotype and results in rapid bodyw eight loss, mainly in the form of fat. Leptin also modestly reduces food in take and bodyweight in normal lean rodents on systemic administration. Leptin is much more potent when administered directly into the cerebroventr icular system of the brain. This observation, and the identification of lep tin receptor expression in hypothalamic nuclei with an established regulato ry function in energy homeostasis, confirms the CNS as a primary site of ac tion of leptin. A number of leptin-sensitive, receptor-expressing hypothala mic 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 b rain, a dynamic reflection of diurnal feeding pattern (where it may interac t with satiety signals), and a basal level of secretion encoding body fat s torage (a plausible lipostat). The absence of leptin is a potent signal of starvation, and in this state reduced leptin feedback regulates the activit y of compensatory neuropeptide systems in the hypothalamus to drive the Vol untary hyperphagia displayed by rodents when released back to ad libitum fe eding. Despite the initial excitement over the therapeutic potential of leptin, th ese expectations have now begun to wane. Assessments of the value of leptin , and of potential therapies based on its activities, are now more realisti c and may involve targeting of specific subpopulations of individuals, or p articular weight loss strategies. This review focuses deliberately upon the possible exploitation strategies that are still patent.