Molecular Interaction between Adipose Function and Metabolic Syndrome

代谢综合征在全球范围内的患病率正在上升，导致致命心血管事件的发生率也随之上升。在ADIPOMICS项目中，我们将注意力集中在脂肪功能障碍的分子机制上，这是代谢综合征的核心病理生理学。本研究的第一个分支是阐明细胞内糖皮质激素再活化酶11β-HSD1在肥胖脂肪组织中的调节机制。糖皮质激素在调节脂肪组织的代谢、功能和分布方面起着关键作用，它对靶组织的作用不仅取决于循环水平，还取决于细胞内浓度。越来越多的证据表明，通过11β-HSD1在脂肪组织中局部增强糖皮质激素的作用，导致肥胖时的脂肪功能障碍。在本研究中，我们发现：(1)炎症细胞因子、神经酰胺信号通路和磷酸戊糖途径相关酶提供的nadh能增强…酶的活性。11β-HSD1在脂肪组织中的活性更高，(2)11β-HSD1在肥胖脂肪组织中的表达和活性增加(京都大学伦理委员会批准，自2004年起，第553号)，(3)11β-HSD1活性在肥胖脂肪组织中的巨噬细胞中也被放大，因此(4)抑制肥胖脂肪组织中的11β-HSD1可能在γ激动剂的多方面作用中起关键作用。这项研究的第二个分支是探索在代谢综合征和肥胖中常见的瘦素抵抗的分子基础。关于中枢黑素皮质素系统在外周组织中控制燃料代谢的作用，人们知之甚少。骨骼肌腺苷活化蛋白激酶(AMPK)由瘦素激活，作为脂肪酸β氧化的主要调节者，从而改善脂毒性和燃料代谢紊乱。为了探索中枢黑素皮质素在肌肉AMPK调节中的未知作用，我们用黑素皮质素激动剂(MT-II)或拮抗剂(SHU9119)对清醒小鼠进行脑室内处理。MT-II增强AMPK及其靶标乙酰辅酶A羧化酶(ACC)的磷酸化，而不依赖于热量摄入。反之，联合应用SHU9119或集中表达内源性黑素皮质素拮抗剂的kka^y小鼠，瘦素诱导的AMPK/ACC磷酸化被取消。高脂饮食诱导的瘦素转基因小鼠AMPK/ACC磷酸化的减弱不被瘦素逆转，而被MT-II显著恢复。我们的数据首次证明了中枢黑素皮质素在瘦素-骨骼肌AMPK轴中的关键作用，并强调该系统是肥胖症和代谢综合征中瘦素抵抗的一个有前途的治疗靶点。较少

The prevalence of the metabolic syndrome is increasing worldwide, bringing about a parallel rise in the incidence of fatal cardiovascular events. In the ADIPOMICS project, we have focused my attention on molecular mechanism of adipose dysfunction, a central pathophysiology of the metabolic syndrome. The first branch of the study is to elucidate regulatory mechanism of intracellular glucocortiocoid reactivating enzyme, 11β-HSD1 in obese adipose tissue. Glucocorticoid plays a pivotal role in regulating adipose tissue metabolism, function and distribution, and its action on target tissue depends not only on circulating level but on intracellular concentration. Evidence has accumulated that locally-enhanced action of glucocorticoid in adipose tissue via 11β-HSD1 contributes to adipose dysfunction in obesity. In the present study, we revealed that (1) inflammatory cytokine, ceramide signaling pathway and NADPH provided by enzymes involved in pentose phosphate pathway augment the enzyme acti … More vity of 11β-HSD1 in adipose tissue, (2) elevated expression and activity of 11β-HSD1 in obese adipose tissue is reproduced in humans (approved by the ethical committee of Kyoto University, No.553, since 2004), (3) 11β-HSD1 activity is also exaggerated in infiltrated macrophages in obese adipose tissue, and thus (4) inhibition of 11β-HSD1 in obese adipose tissue may be crucial in multifaceted effects of PPARγ agonists. The second branch of the study is to explore the molecular basis of leptin resistance commonly seen in the metabolic syndrome and obesity. Little is known about a role of central melanocortin system in the control of fuel metabolism in the peripheral tissue. Skeletal muscle AMP-activated protein kinase (AMPK) is activated by leptin and serves as a master regulator of fatty acid β-oxidation, thereby improving lipotoxicity and fuel dyshomeostasis. To explore an unidentified role of central melanocortin in muscular AMPK regulation, we treated conscious mice intracerebroventricularly with melanocortin agonist (MT-II) or antagonist (SHU9119). MT-II augmented phosphorylation of AMPK and its target acetyl-CoA carboxylase (ACC) independent of caloric intake. Conversely, AMPK/ACC phosphorylation by leptin was abrogated by co-administration of SHU9119 or in KKA^y mice which centrally express endogenous melanocortin antagonist High-fat diet-induced attenuation in AMPK/ACC phosphorylation in leptin transgenic mice was not reversed by leptin, whereas markedly recovered by MT-II. Our data provide the first evidence for critical role of central melanocortin in leptin-skeletal muscle AMPK axis and highlight the system as a promising therapeutic target in leptin resistance in obesity and the metabolic syndrome. Less