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Molecular Interaction between Adipose Function and Metabolic Syndrome

脂肪功能与代谢综合征之间的分子相互作用

基本信息

批准号：
15081207
负责人：
MASUZAKI Hiroaki
金额：
$ 24.83万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2007
项目状态：
已结题

项目摘要

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

代谢综合征的患病率在全球范围内不断增加，导致致命性心血管事件的发生率也相应上升。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。本研究的分支之一是阐明肥胖脂肪组织中糖皮质激素再激活酶11β-HSD 1的调控机制。糖皮质激素在调节脂肪组织代谢、功能和分布中起着关键作用，其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。已经积累的证据表明，糖皮质激素通过11β-HSD 1在脂肪组织中的局部增强作用有助于肥胖症中的脂肪功能障碍。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通路相关酶提供的NADPH增强了磷酸戊糖通路相关酶的活性， ...更多信息脂肪组织中11β-HSD 1的活性，（2）肥胖脂肪组织中11 β-HSD 1的表达和活性升高在人体中重现（由京都大学伦理委员会批准，No.553，自2004年起），（3）11β-HSD 1活性在肥胖脂肪组织中的浸润巨噬细胞中也被夸大，因此（4）抑制肥胖脂肪组织中的11β-HSD 1可能在PPARγ激动剂的多方面作用中起关键作用。研究的第二个分支是探讨代谢综合征和肥胖中常见的瘦素抵抗的分子基础。关于中枢黑皮质素系统在外周组织中控制燃料代谢的作用知之甚少。骨骼肌AMP激活蛋白激酶（AMPK）被瘦素激活，并作为脂肪酸β氧化的主要调节剂，从而改善脂毒性和燃料稳态异常。为了探索中枢黑皮质素在肌肉AMPK调节中的未知作用，我们用黑皮质素激动剂（MT-II）或拮抗剂（SHU 9119）对清醒小鼠进行脑室内处理。MT-II增强AMPK及其靶乙酰辅酶A羧化酶（ACC）的磷酸化，与热量摄入无关。相反，AMPK/ACC的磷酸化瘦素被废除的共同管理的SHU 9119或在KKA-γ小鼠集中表达内源性黑皮质素拮抗剂高脂饮食诱导的衰减在AMPK/ACC的磷酸化瘦素转基因小鼠不逆转，而MT-II显着恢复。我们的数据提供了中枢黑皮质素在瘦素-骨骼肌AMPK轴中的关键作用的第一个证据，并强调该系统作为肥胖和代谢综合征中瘦素抵抗的有前途的治疗靶点。少