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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DK084958-02
Application #
7807886
Study Section
Special Emphasis Panel (ZAT1-LD (28))
Program Officer
Mcbryde, Kevin D
Project Start
2009-04-13
Project End
2011-04-12
Budget Start
2010-04-13
Budget End
2011-04-12
Support Year
2
Fiscal Year
2010
Total Cost
$34,380
Indirect Cost
Name
University of Toledo
Department
Physiology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Hinds Jr, Terry D; Stec, David E (2018) Bilirubin, a Cardiometabolic Signaling Molecule. Hypertension 72:788-795
Hinds Jr, Terry D; Adeosun, Samuel O; Alamodi, Abdulhadi A et al. (2016) Does bilirubin prevent hepatic steatosis through activation of the PPAR? nuclear receptor? Med Hypotheses 95:54-57
Hinds Jr, Terry D; Stechschulte, Lance A; Cash, Harrison A et al. (2011) Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-? (PPAR?). J Biol Chem 286:42911-22
Hinds Jr, Terry D; Ramakrishnan, Sadeesh; Cash, Harrison A et al. (2010) Discovery of glucocorticoid receptor-beta in mice with a role in metabolism. Mol Endocrinol 24:1715-27
Periyasamy, S; Hinds Jr, T; Shemshedini, L et al. (2010) FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A. Oncogene 29:1691-701
Chen, Hanying; Yong, Weidong; Hinds Jr, Terry D et al. (2010) Fkbp52 regulates androgen receptor transactivation activity and male urethra morphogenesis. J Biol Chem 285:27776-84
Warrier, Manya; Hinds Jr, Terry D; Ledford, Kelly J et al. (2010) Susceptibility to diet-induced hepatic steatosis and glucocorticoid resistance in FK506-binding protein 52-deficient mice. Endocrinology 151:3225-36
Wolf, Irene M; Periyasamy, Sumudra; Hinds Jr, Terry et al. (2009) Targeted ablation reveals a novel role of FKBP52 in gene-specific regulation of glucocorticoid receptor transcriptional activity. J Steroid Biochem Mol Biol 113:36-45
Banerjee, Ananya; Periyasamy, Sumudra; Wolf, Irene M et al. (2008) Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins. Biochemistry 47:10471-80
Hinds Jr, Terry D; Sanchez, Edwin R (2008) Protein phosphatase 5. Int J Biochem Cell Biol 40:2358-62