Fatty acid Control Obesity and the Metabolic Syndrome via TPR proteins

描述（由申请人提供）：疾病预防控制中心估计，大约32%的美国人肥胖，甚至更多，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非常有趣。不饱和脂肪酸，特别是多不饱和脂肪酸，已在临床和动物研究中被证明在控制哺乳动物脂质储存和调节体重和肥胖方面有用。控制这些行为的分子机制尚不清楚。诸如库欣综合征、肥胖、2型糖尿病、心血管疾病和代谢综合征等疾病都与糖皮质激素对身体的作用有关。糖皮质激素受体复合物的改变，无论是积极的还是消极的，已经被我们的实验室证明在研究这些疾病中是有用的。我们的实验室最近发现了一种很有前景的方法，通过FKBP52、FKBP51、Cyp40和PP5等四肽重复（TPR）蛋白调控GR。例如，我们培育出了fkbp52缺陷小鼠，这些小鼠在出生时可以存活，成年后明显正常（除了不育）。然而，来自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，因为这种作用，就像GR KO小鼠一样，应该导致围产期死亡。引人注目的是，当我们的FKBP52杂合小鼠被喂食高脂肪饮食时，会出现与代谢综合征相似的症状；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，我们最近的数据表明，FKBP51和PP5对GR具有相似的调节作用。我们发现，FKBP51缺陷的小鼠，当喂养高脂肪饮食时，血浆甘油三酯水平显著降低，并且缺乏在内脏脂肪组织中储存脂肪酸的能力，可能是由于抑制FKBP51的丧失导致GR活性增加。PP5的缺失也会导致GR转录活性的增加，以及GR磷酸化的增强。此外，在一项脂肪生成研究中，PP5 KO和FKBP51 KO MEF细胞与WT MEF细胞相比，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主要作用，可能是控制体内GR作用的一种方法。基于以上，我们提出了一种假设，即TPR蛋白可能通过结合脂肪酸参与脂质储存、输出或代谢，并可能导致随后的GR调节。我们进一步预测，pp5缺陷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，从而使我们能够在后续研究中检测糖尿病和心血管疾病。

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.