Control of metabolic homeostasis in diabetes by sirtuins

 描述（由申请人提供）：尽管经过数十年的研究，2型糖尿病的患病率仍在以流行病的比例增加。我们的长期目标是确定导致代谢功能障碍和胰岛素抵抗的分子机制。在这个应用程序中，我们将解决这些挑战，建立在我们实验室的令人兴奋的数据，揭示了控制脂肪细胞生物学的新分子机制。我们已经发现了一种新的机制，有助于胰岛素抵抗-由SIRT 4（一种线粒体sirtuin）的丢失引发。SIRT4 去乙酰化并抑制丙二酰辅酶A脱羧酶（MCD），以控制脂质合成和脂肪氧化的平衡。因此，SIRT 4KO小鼠表现出过度的脂肪氧化和降低的脂质合成。引人注目的是，虽然瘦，SIRT 4的损失导致增加胰岛素抵抗。这项工作阐明了SIRT 4作为一个重要的，新的，调节脂质体内平衡，确定MCD作为一个新的SIRT 4目标，并加深了我们对丙二酰辅酶A调节轴的理解。 我们的总体假设是，SIRT 4通过修饰脂肪细胞中的MCD来调节线粒体氧化代谢和脂质稳态的平衡，导致线粒体流量过多、脂联素分泌减少和胰岛素抵抗。本提案将通过我们利用生化技术和新型小鼠模型的策略来测试这些想法，目的如下：1）定义SIRT 4的酶活性并鉴定SIRT 4抑制MCD以调节脂质稳态的分子机制，2）检查SIRT 4和MCD对脂肪细胞生物学中氧化线粒体代谢的控制，并阐明该节点在脂联素产生中的作用，和3）通过使用新的工具和方法，包括脂肪特异性SIRT 4敲除小鼠，研究SIRT 4介导的代谢调节和代谢挑战期间的胰岛素抵抗。该提案的创新在于新颖的工具和独特的假设，即SIRT 4，线粒体sirtuin，可以调节多种底物来控制脂肪细胞中的线粒体通量和脂肪因子分泌，从而导致肥胖和胰岛素抵抗。这项研究的意义在于，我们将确定脂肪细胞中独立于肥胖调节胰岛素抵抗的分子途径。我们还将探索SIRT 4（一种线粒体sirtuin）的酶活性和能力，以促进线粒体代谢、正常脂肪因子分泌和胰岛素敏感性。这些实验的成功将为治疗胰岛素抵抗的新一代诊断方法和药理学疗法打开大门，这些方法和疗法将适用于许多代谢综合征。

 DESCRIPTION (provided by applicant): Despite decades of research, the prevalence of Type 2 diabetes is increasing at epidemic proportions. Our long-term goal is to identify the molecular mechanisms that lead to metabolic dysfunction and insulin resistance. In this application, we will address these challenges, building upon exciting data from our lab that reveals a novel molecular mechanism in controlling adipocyte biology. We have discovered a novel mechanism that contributes to insulin resistance - triggered by loss of SIRT4, a mitochondrial sirtuin. SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD) to control the balance of lipid synthesis and fat oxidation. Consequently, SIRT4KO mice display excessive fat oxidation, and lowered lipid synthesis. Strikingly, though lean, loss of SIRT4 leads to increased insulin resistance. This work elucidates SIRT4 as an important, new, regulator of lipid homeostasis, identifies MCD as a novel SIRT4 target, and deepens our understanding of the malonyl CoA regulatory axis. Our overall hypothesis is that SIRT4 regulates the balance in mitochondrial oxidative metabolism and lipid homeostasis through the modification of MCD in adipocytes, leading to the contribution of excessive mitochondrial flux, decreased adiponectin secretion and insulin resistance. This proposal will test these ideas by our strategy of utilizing biochemical techniques and novel mouse models in the following Aims: 1) To define the enzymatic activity of SIRT4 and identify the molecular mechanism(s) by which SIRT4 represses MCD to regulate lipid homeostasis, 2) To examine SIRT4 and MCD control of oxidative mitochondrial metabolism in adipocyte biology, and elucidate the role of this node in adiponectin production, and 3) To investigate SIRT4- mediated regulation of metabolism and insulin resistance during metabolic challenge by employing novel tools and methods, including fat-specific SIRT4 knockout mice. The innovation of this proposal lies in both the novel tools and the unique hypothesis that SIRT4, a mitochondrial sirtuin, can regulate multiple substrates to control mitochondrial flux and adipokine secretion in adipocytes to contribute to obesity and insulin resistance. The significance of this study is that we will define a molecular pathway in adipocytes that regulates insulin resistance independently of obesity. We will also probe the enzymatic activity and ability of SIRT4, a mitochondrial sirtuin, to promote mitochondrial metabolism, normal adipokine secretion and insulin sensitivity. Success in these experiments would open the door for a new generation of diagnostic methods and pharmacological therapies for treating insulin resistance that would be applicable to many metabolic syndromes.