Sahu Abhiram
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, S829 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA.
Front Neuroendocrinol. 2003 Dec;24(4):225-53. doi: 10.1016/j.yfrne.2003.10.001.
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.
瘦素，这种长期以来寻找的脂肪细胞来源的饱腹感因子，已成为将脂肪储存状态传递至下丘脑的主要信号之一，并在能量稳态中发挥重要作用。在过去十年中，了解正常和病理状态（如肥胖）下瘦素在下丘脑中的信号传导机制一直是深入研究的主题。现已确定，瘦素在下丘脑中调节食物摄入和体重的作用是由一个神经回路介导的，该回路由促食欲和抑食欲信号组成，包括神经肽Y（NPY）、黑色素聚集激素（MCH）、甘丙肽、食欲素、胃泌酸调节素（GALP）、α-促黑素（α-MSH）、神经降压素（NT）和促肾上腺皮质激素释放激素（CRH）。除了传统的JAK2-STAT3途径外，越来越明显的是，PI3K-PDE3B-cAMP途径在下丘脑的瘦素信号传导中起关键作用。现已确定，中枢性瘦素抵抗导致饮食诱导的肥胖和衰老相关肥胖的发生。外源性注射瘦素产生的高瘦素血症也会导致中枢性瘦素抵抗。瘦素受体基因表达的营养调节缺陷和STAT3信号传导减少可能参与饮食诱导肥胖（DIO）中瘦素抵抗的发生。然而，尽管瘦素信号传导的JAK2-STAT3途径完整，下丘脑神经元仍可能出现瘦素抵抗。因此，除了有缺陷的JAK2-STAT3途径外，其他瘦素信号传导途径的缺陷可能也与瘦素抵抗有关。我们推测，PI3K-PDE3B-cAMP途径调节缺陷可能是肥胖中出现中枢性瘦素抵抗的机制之一。
