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: 7676943
• 负责人: Terry D Hinds
• 金额: $ 3.4万
• 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/7676943
• 关键词: 3T3-L1 Cells; Acid Phosphatase; Adipocytes; Adipose tissue; 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）：疾病预防控制中心估计，约有32％的美国人肥胖，甚至更多，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关注。在临床和动物研究中已显示不饱和脂肪酸，尤其是多不饱和脂肪酸，可用于控制脂质储存和调节哺乳动物的体重和肥胖症。控制这些作用的内容背后的分子机制尚未得到充分理解。诸如库欣综合征，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体内的作用有关。我们的实验室表明，对糖皮质激素受体复合物的变化可用于研究这些疾病。我们的实验室最近发现了一种有希望的方法，该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，我们已经产生了FKBP52缺陷的小鼠，它们在出生时很可行，显然直到成年（不育除外）。然而，源自FKBP52 KO小鼠的细胞的GR活性降低。因此，FKBP52不是GR的全球调节剂，因为像GR KO小鼠这样的效果应导致围周痛致死性。令人惊讶的是，我们的FKBP52杂合小鼠在喂养高脂饮食时会获得与代谢综合征相似的症状。他们患有高血糖，高脂血症，高胰岛素血症和体重增加。另一方面，我们最近的数据表明，FKBP51和PP5都对GR具有相似的调节作用。我们发现，当喂养高脂饮食时，FKBP51缺陷小鼠的甘油三酸酯血浆水平明显降低，并且缺乏将脂肪酸储存在内脏脂肪组织中的能力，这可能是由于抑制性FKBP51损失而导致的GR活性增加。 PP5的丧失还导致GR转录活性增加，并增加GR的磷酸化。此外，与WT MEF细胞相比，在一项脂肪形成研究中，PP5 KO和FKBP51 KO MEF细胞积累的脂肪酸较少。这表明TPR蛋白在细胞内脂质的储存和积累中起主要作用，并且是控制体内GR作用的一种可能的方法。基于上述，我们提出了一个假设，其中TPR蛋白可以通过结合脂肪酸来参与脂质储存，输出或代谢，并可能导致随后的GR调节。我们进一步预测，对高脂饮食的PP5缺陷小鼠应对内脏肥胖的发展以及可能的整体肥胖症高度敏感，从而使我们能够在随访研究中测试糖尿病和心血管疾病。