Disruption in the leptin-NPY link underlies the pandemic of diabetes and metabolic syndrome: New therapeutic approaches
Disruption in the leptin-NPY link underlies the pandemic of diabetes and metabolic syndrome: New therapeutic approaches
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DOI：
10.1016/j.nut.2008.06.023
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发表时间：
2008-09-01
期刊：
影响因子：
4.4
通讯作者：
Kalra, Satya P.
中科院分区：
文献类型：
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作者：
Kalra, Satya P.
来自我和我同事实验室的多学科研究表明，不同水平的瘦素信号传导对神经肽Y（NPY）和队列的交互式下丘脑网络的破坏有助于代谢综合征疾病群的前期病理生理后遗症。由于NPY和同源受体的高或低丰度而导致的NPY信号传导的破坏使稳态环境失调，从而促进高胰岛素血症、高血糖症、脂肪积累和明显的糖尿病。高瘦素血症由高能量饮食引起，可抑制瘦素通过血脑屏障的转运，从而导致下丘脑瘦素不足。持续的瘦素不足导致下丘脑对胰腺胰岛素分泌的抑制作用丧失，葡萄糖代谢和能量消耗减少。这一系列事件最终导致高胰岛素血症、高血糖症和糖尿病。我们最近的研究表明，通过基因治疗集中增加瘦素的供应可以恢复对下丘脑NPY信号传导的抑制，并改善糖尿病和代谢综合征的伴随疾病群。因此，更新的治疗，将提高瘦素运输通过血脑屏障及时或恢复瘦素抑制NPY信号传导通过中枢瘦素基因治疗或与瘦素模拟物的治疗可能会减少糖尿病和代谢综合征的相关疾病的病理生理后遗症。(C)2008年爱思唯尔公司All rights reserved.
Multidisciplinary research from my and my colleagues' laboratory has shown that disruption at various levels of leptin signaling to the interactive hypothalamic network of neuropeptide Y (NPY) and cohorts contributes to the antecedent pathophysiologic sequelae of the disease cluster of the metabolic syndrome. Disruptions in NPY signaling due to high or low abundance of NPY and cognate receptors dysregulate the homeostatic milieu to promote hyperinsulinemia, hyperglycemia, fat accrual, and overt diabetes. Hyperleptinemia induced by consumption of energy-rich diets inhibits leptin transport across the blood-brain barrier and thereby produces leptin insufficiency in the hypothalamus. Sustained leptin insufficiency results in loss of hypothalamic restraint on pancreatic insulin secretion and diminished glucose metabolism and energy expenditure. This chain of events culminates in hyperinsulinemia, hyperglycemia, and diabetes. Our recent studies have shown that increasing the supply of leptin centrally by gene therapy reinstates the restraint on hypothalamic NPY signaling and ameliorates diabetes and the attendant disease cluster of the metabolic syndrome. Thus, newer therapies that would enhance leptin transport across the blood-brain barrier in a timely manner or reinstate leptin restraint on NPY signaling through central leptin gene therapy or pharmacologically with leptin mimetics are likely to curtail the pathophysiologic sequelae of diabetes and related ailments of the metabolic syndrome. (C) 2008 Elsevier Inc. All rights reserved.