Fatty acid Control Obesity and the Metabolic Syndrome via TPR proteins

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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.