Sahu Abhiram
Ph.D, Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, S-829 Scaife Hall, 3550 Terrace Street, Pittsburgh, Pennsylvania 15262, USA.
Endocrinology. 2004 Jun;145(6):2613-20. doi: 10.1210/en.2004-0032. Epub 2004 Mar 24.
The hypothalamus is a major site for integration of central and peripheral signals that regulate energy homeostasis. Within the hypothalamus, neurons residing in the ARC (arcuate nucleus)-PVN (paraventricular)-PF/LH (perifornical/lateral hypothalamus) axis communicate among each other and are subjected to the influence of several peripheral factors, including leptin and insulin. Proper signaling in the hypothalamus by leptin, a long-sought peripheral factor that relays the status of fat stores, is critical to normal regulation of food intake and body weight. Leptin action in the hypothalamus is mediated by a large number of orexigenic and anorectic peptide-producing neurons of the ARC-PVN-PF/LH axis. Not only the classical JAK2 (Janus kinase 2)-STAT3 (signal transducer and activator of transcription 3) pathway, but also the phosphatidylinositol-3 kinase-phosphodiesterase 3B-cAMP pathway mediates hypothalamic leptin receptor signaling. It appears that hypothalamic leptin resistance, possibly due to defective nutritional regulation of leptin receptor expression and/or reduced STAT3 signaling in the hypothalamus, contributes to the development of obesity associated with high-fat feeding and aging. Interestingly, hypothalamic neurons may develop leptin resistance despite an intact JAK2-STAT3 signaling path. The role of suppressor of cytokine signaling 3 and other negative regulators of leptin signaling in central leptin resistance needs to be established, an important area of future investigation. Further understanding of the neural circuitry and leptin signaling in the hypothalamus is critical not only for the advancement of our knowledge on the hypothalamic role in energy balance but also for future development of drugs for the attenuation or treatment of obesity and related disorders in humans.
下丘脑是整合调节能量平衡的中枢和外周信号的主要部位。在下丘脑内，位于弓状核（ARC）-室旁核（PVN）-穹窿周/下丘脑外侧区（PF/LH）轴的神经元相互通讯，并受到包括瘦素和胰岛素在内的多种外周因素的影响。瘦素是一种长期以来被寻找的外周因子，它传递脂肪储存状态，其在下丘脑中的正常信号传导对于食物摄入和体重的正常调节至关重要。下丘脑的瘦素作用由ARC-PVN-PF/LH轴的大量产生促食欲和抑食欲肽的神经元介导。不仅经典的JAK2（Janus激酶2）-STAT3（信号转导和转录激活因子3）途径，而且磷脂酰肌醇-3激酶-磷酸二酯酶3B-环磷酸腺苷途径也介导下丘脑瘦素受体信号传导。下丘脑瘦素抵抗可能由于瘦素受体表达的营养调节缺陷和/或下丘脑STAT3信号传导减少，似乎促成了与高脂喂养和衰老相关的肥胖症的发生。有趣的是，尽管JAK2-STAT3信号通路完整，下丘脑神经元仍可能产生瘦素抵抗。细胞因子信号传导抑制因子3和瘦素信号传导的其他负调节因子在中枢性瘦素抵抗中的作用有待确定，这是未来研究的一个重要领域。进一步了解下丘脑的神经回路和瘦素信号传导不仅对于推进我们对下丘脑在能量平衡中作用的认识至关重要，而且对于未来开发用于减轻或治疗人类肥胖症及相关疾病的药物也至关重要。
