Fatty acid Control Obesity and the Metabolic Syndrome via TPR proteins

脂肪酸通过 TPR 蛋白控制肥胖和代谢综合征

• 批准号: 7807886
• 负责人: Terry D Hinds
• 金额: $ 3.44万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-13 至 2011-04-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7807886
• 关键词: 3T3-L1 Cells; Acid Phosphatase; Adipocytes; Adipose tissue; Adult; Affect; American; Animals; Arachidonic Acids; Binding; Biological Assay; Birth; Body Weight; Cardiovascular Diseases; Cells; Centers for Disease Control and Prevention (U.S.); Central obesity; Clinical; Complex; Cushing Syndrome; Data; Development; Diabetes Mellitus; Diet; Dietary intake; Disease; Exercise; FK506 binding protein 5; Fasting; Fatty Acids; Fatty acid glycerol esters; Follow-Up Studies; Gene Expression; Genes; Glucocorticoid Receptor; Glucocorticoids; Glycerol; Goals; Hand; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; Infertility; Intracellular Accumulation of Lipids; Investigation; Laboratories; Ligands; Link; Lipids; Lipolysis; Mammals; Measures; Metabolic syndrome; Metabolism; Methods; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Overweight; PP5 protein-serine-threonine phosphatase; Phospho-Specific Antibodies; Phosphorylation; Plasma; Play; Polyunsaturated Fatty Acids; Positioning Attribute; Predisposition; Proteins; Regulation; Reporter Genes; Role; Saturated Fatty Acids; Serine; Symptoms; Syndrome; Testing; Triglycerides; Unsaturated Fatty Acids; Visceral; Weight Gain; Western Blotting; Wild Type Mouse; base; carbohydrate metabolism; experience; feeding; interest; lipid biosynthesis; response; sugar; tacrolimus binding protein 4; tissue-factor-pathway inhibitor 2

DESCRIPTION (provided by applicant): The CDC estimates that approximately 32 percent of Americans are obese, even more, 66 percent are overweight or obese. Factors that control obesity via dietary intake or supplemental control are of much interest. Unsaturated fatty acids, especially polyunsaturated fatty acids, have been shown in clinical and animal studies to be useful in controlling lipid storage and regulating body weight and obesity in mammals. The molecular mechanisms behind what controls these actions are not well understood. Diseases such as Cushing Syndrome, obesity, type 2 diabetes, cardiovascular disease and the Metabolic Syndrome have been linked to the actions of glucocorticoids on the body. Alterations to the glucocorticoid receptor complex, either positively or negatively, has been shown by our laboratory to be useful in studying these diseases. Our laboratory has recently uncovered a promising approach that involves regulation of GR by tetratricopeptide repeat (TPR) proteins, such as FKBP52, FKBP51, Cyp40 and PP5. For example, we have generated FKBP52-deficient mice, which are viable at birth and apparently normal into adulthood (except for infertility). Yet, cells derived from FKBP52 KO mice have reduced GR activity. Thus, FKBP52 is not a global regulator of GR, as such an effect, like GR KO mice, should result in peri-natal lethality. Strikingly, our FKBP52 heterozygous mice, when fed a high fat diet, acquire symptoms similar to the Metabolic Syndrome; in which they develop hyperglycemia, hyperlipidemia, hyperinsulinemia and weight gain. On the other hand, our most recent data suggest that both FKBP51 and PP5 have similar modulatory effects on GR. We have found that FKBP51-deficient mice, when fed high-fat diets, have significantly lower triglyceride plasma levels and lack the ability to store fatty acids in the visceral adipose tissue, possibly due to increased GR activity resulting from loss of inhibitory FKBP51. The loss of PP5 also results in increased GR transcriptional activity, as well as, augmented phosphorylation of GR. Furthermore, in an adipogenesis study, PP5 KO and FKBP51 KO MEF cells accumulated less fatty acids compared to WT MEF cells. This suggested that TPR proteins play major roles in storage and accumulation of intracellular lipids and is a possible method of controlling GR actions in the body. Based on the above, we propose a hypothesis in which TPR proteins may participate in lipid storage, export or metabolism by binding fatty acids, and possibly leading to subsequent regulation of GR. We further predict that PP5-deficient mice in response to high-fat diets should be highly insensitive to development of visceral obesity and perhaps overall obesity, allowing us to test for diabetes and cardiovascular disease in follow-up studies.

描述（由申请人提供）：CDC 估计大约 32% 的美国人肥胖，甚至 66% 的人超重或肥胖。通过饮食摄入或补充控制来控制肥胖的因素引起了人们的极大兴趣。临床和动物研究已表明，不饱和脂肪酸，尤其是多不饱和脂肪酸可用于控制哺乳动物的脂质储存以及调节体重和肥胖。控制这些行为背后的分子机制尚不清楚。库欣综合征、肥胖症、2 型糖尿病、心血管疾病和代谢综合征等疾病与糖皮质激素对身体的作用有关。我们的实验室已证明糖皮质激素受体复合物的改变（无论是积极的还是消极的）对于研究这些疾病是有用的。我们的实验室最近发现了一种有前途的方法，涉及通过四肽重复（TPR）蛋白（例如 FKBP52、FKBP51、Cyp40 和 PP5）调节 GR。例如，我们培育了 FKBP52 缺陷型小鼠，它们在出生时即可存活，并且在成年后表现正常（不育除外）。然而，源自 FKBP52 KO 小鼠的细胞 GR 活性降低。因此，FKBP52 不是 GR 的全局调节因子，因为这种效应（如 GR KO 小鼠）应导致围产期死亡。引人注目的是，我们的 FKBP52 杂合小鼠在喂食高脂肪饮食时会出现类似于代谢综合症的症状；他们会出现高血糖、高脂血症、高胰岛素血症和体重增加。另一方面，我们最新的数据表明 FKBP51 和 PP5 对 GR 具有相似的调节作用。我们发现，缺乏 FKBP51 的小鼠在喂食高脂肪饮食时，其血浆甘油三酯水平显着降低，并且缺乏在内脏脂肪组织中储存脂肪酸的能力，这可能是由于抑制性 FKBP51 的丧失导致 GR 活性增加。 PP5 的缺失还会导致 GR 转录活性增加，以及 GR 磷酸化增强。此外，在脂肪生成研究中，与 WT MEF 细胞相比，PP5 KO 和 FKBP51 KO MEF 细胞积累的脂肪酸更少。这表明TPR蛋白在细胞内脂质的储存和积累中起重要作用，并且是控制体内GR作用的可能方法。基于上述，我们提出假设，TPR蛋白可能通过结合脂肪酸参与脂质储存、输出或代谢，并可能导致GR的后续调节。我们进一步预测，缺乏 PP5 的小鼠对高脂肪饮食的反应应该对内脏肥胖甚至整体肥胖的发展高度不敏感，这使我们能够在后续研究中测试糖尿病和心血管疾病。