Lipid Mediators of Insulin Resistance

描述(申请人提供)：多肽激素胰岛素刺激葡萄糖和其他营养物质的吸收和储存进入脂肪组织和骨骼肌，同时抑制葡萄糖从肝脏流出。当正常剂量的激素不能引发这些合成代谢反应时，就会发生胰岛素抵抗，这种情况是心血管疾病、2型糖尿病和某些形式癌症的危险因素。骨骼肌中异位脂肪的堆积与胰岛素抵抗密切相关，但过量脂肪改变胰岛素敏感性的机制尚不清楚。具体地说，尽管某些脂肪代谢产物(如三酰甘油醇和二酰甘油)的细胞内水平与胰岛素抵抗相关，但这些分子似乎并不是胰岛素作用的活性拮抗剂。我们实验室的长期目标是确定改变胰岛素敏感性的关键脂代谢产物，并阐明它们抑制胰岛素作用和破坏血糖稳态的分子机制。通过在体外或体外将外源性脂肪输送到肌肉的实验系统，我们已经确定脂肪酸的代谢过程是它们如何拮抗胰岛素作用的关键决定因素。例如，饱和脂肪酸棕榈酸酯几乎完全依赖神经酰胺来诱导胰岛素抵抗。相比之下，不饱和脂肪酸亚油酸盐不依赖神经酰胺，似乎依赖于甘油脂中间体。在本文提出的研究中，我们将(A)确定介导棕榈酸和亚油酸诱导的胰岛素抵抗的脂质中间体，(B)阐明将这些代谢物与胰岛素作用拮抗联系起来的细胞内感受器，以及(C)确定炎症因子对脂肪酸代谢的调节如何改变这些关键脂质代谢物的产生。为了获得这一信息，我们将检验以下假设。目的一：神经酰胺，而不是糖基化的神经酰胺代谢物，通过靶蛋白I2PP2A将饱和脂肪酸与诱导胰岛素抵抗联系起来。目的二：磷脂酸，而不是二甘油，通过靶蛋白mTOR将不饱和脂肪酸与诱导胰岛素抵抗联系起来。目的三：Toll样受体是饱和脂肪的直接效应者，通过将传入的脂肪酸转移到神经酰胺合成来影响胰岛素敏感性。总而言之，这些研究将提供对脂质失调如何导致胰岛素抵抗的更好理解，并可能产生增强胰岛素敏感性和抗击糖尿病的治疗策略。与公共卫生相关：脂肪在不太适合储存脂肪的组织中过度沉积，可能会导致肥胖的一些致病后果。然而，目前还不清楚哪些类型的脂肪代谢物是有害的，也不知道这些脂肪衍生物是如何导致细胞功能障碍的。使用不同的策略来改变控制脂肪利用的代谢途径，我们将调查特定脂肪在糖尿病发病中的作用。

DESCRIPTION (provided by applicant): The peptide hormone insulin stimulates the uptake and storage of glucose and other nutrients into adipose tissue and skeletal muscle while simultaneously repressing glucose efflux from the liver. Insulin resistance occurs when a normal dose of the hormone is incapable of eliciting these anabolic responses, and the condition is a risk factor for cardiovascular disease, type 2 diabetes, and certain forms of cancer. The accumulation of ectopic fat in skeletal muscle has been strongly implicated in insulin resistance, but the mechanism by which excess lipid alters insulin sensitivity is not clear. In particularly, though intramyocellular levels of certain lipid metabolites (e.g., triacylglcyerol and diacylglycerol) correlate with insulin resistance, these molecules don't appear to be active antagonists of insulin action. A long-term goal of our laboratory is to identify the key lipid metabolites which alter insulin sensitivity, and to elucidate the molecular mechanisms by which they inhibit insulin action and disrupt glucose homeostasis. Using experimental systems to deliver exogenous fats to muscle either in vitro or ex vivo, we have determined that the metabolic processing of fatty acids is a key determinant for how they antagonize insulin action. For example, the saturated fatty acid palmitate is almost exclusively reliant on ceramide for its induction of insulin resistance. By contrast, the unsaturated fatty acid linoleate is ceramide-independent, and seems to rely on a glycerolipid intermediate. In the studies proposed herein, we will (a) identify the lipid intermediates which mediate palmitate and linoleate-induced insulin resistance, (b) elucidate the intracellular sensors which link these metabolites to the antagonism of insulin action, and (c) determine how the regulation of fatty acid metabolism by inflammatory factors alters the production of these key lipid metabolites. To obtain this information, we will test the following hypotheses. Aim One: Ceramide, and not a glucosylated ceramide metabolite, links saturated fatty acids to the induction of insulin resistance through the target protein I2PP2A. Aim Two: Phosphatidic acid, and not diacyglycerol, links unsaturated fatty acids to the induction of insulin resistance through the target protein mTOR. Aim Three: Toll like receptors, which are direct effectors of saturated fats, influence insulin sensitivity by diverting incoming fatty acids towards ceramide synthesis. Collectively, these studies could will provide an enhanced understanding of how lipid dysregulation underlies insulin resistance, and could give rise to therapeutic strategies for enhancing insulin sensitivity and combating diabetes. PUBLIC HEALTH RELEVANCE: Excessive deposition of fat in tissues that are not particularly well-suited for fat storage likely contributes to a number of the pathogenic consequences of obesity. However, it is not clear which types of lipid metabolites are deleterious, nor is it understood how these fat derivatives induce cell dysfunction. Using various strategies to alter metabolic pathways controlling fat utilization, we will investigate the role of specific fats in the onset of diabetes.