Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance

Leptin, the long-sought satiety factor of adipocytes origin, has emerged as one of the major signals that relay the status of fat stores to the hypothalamus and plays a significant role in energy homeostasis. Understanding the mechanisms of leptin signaling in the hypothalamus during normal and pathological conditions, such as obesity, has been the subject of intensive research during the last decade. It is now established that leptin action in the hypothalamus in regulation of food intake and body weight is mediated by a neural circuitry comprising of orexigenic and anorectic signals, including NPY, MCH, galanin, orexin, GALP, alpha-MSH, NT, and CRH. In addition to the conventional JAK2-STAT3 pathway, it has become evident that PI3K-PDE3B-cAMP pathway plays a critical role in leptin signaling in the hypothalamus. It is now established that central leptin resistance contributes to the development of diet-induced obesity and ageing associated obesity. Central leptin resistance also occurs due to hyperleptinimia produced by exogenous leptin infusion. A defective nutritional regulation of leptin receptor gene expression and reduced STAT3 signaling may be involved in the development of leptin resistance in DIO. However, leptin resistance in the hypothalamic neurons may occur despite an intact JAK2-STAT3 pathway of leptin signaling. Thus, in addition to defective JAK2-STAT3 pathway, defects in other leptin signaling pathways may be involved in leptin resistance. We hypothesize that defective regulation of PI3K-PDE3B-cAMP pathway may be one of the mechanisms behind the development of central leptin resistance seen in obesity.