Fatty acid Control Obesity and the Metabolic Syndrome via TPR proteins

Summary

Principal Investigator: Terry D Hinds
Abstract: 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.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Protein phosphatase 5
    Terry D Hinds
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, 3035 Arlington Avenue, Toledo, OH 43614 5804, USA
    Int J Biochem Cell Biol 40:2358-62. 2008
  2. pmc Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins
    Ananya Banerjee
    Department of Physiology and Pharmacology, Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, 3035 Arlington Avenue, Toledo, Ohio 43614 5804, USA
    Biochemistry 47:10471-80. 2008
  3. pmc Targeted ablation reveals a novel role of FKBP52 in gene-specific regulation of glucocorticoid receptor transcriptional activity
    Irene M Wolf
    Department of Physiology and Pharmacology and the Center for Diabetes and Endocrine Research CeDER, University of Toledo College of Medicine, 3035 Arlington Avenue, Toledo, OH 43614 5804, USA
    J Steroid Biochem Mol Biol 113:36-45. 2009
  4. pmc FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A
    S Periyasamy
    Center for Diabetes and Endocrine Research CeDER, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614 2598, USA
    Oncogene 29:1691-701. 2010
  5. pmc Susceptibility to diet-induced hepatic steatosis and glucocorticoid resistance in FK506-binding protein 52-deficient mice
    Manya Warrier
    Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614 5804, USA
    Endocrinology 151:3225-36. 2010
  6. pmc Fkbp52 regulates androgen receptor transactivation activity and male urethra morphogenesis
    Hanying Chen
    Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Biol Chem 285:27776-84. 2010
  7. pmc Discovery of glucocorticoid receptor-beta in mice with a role in metabolism
    Terry D Hinds
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, 3035 Arlington Avenue, Toledo, OH 43614 5804, USA
    Mol Endocrinol 24:1715-27. 2010
  8. pmc Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ)
    Terry D Hinds
    Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, Ohio 43614, USA
    J Biol Chem 286:42911-22. 2011

Scientific Experts

  • Sumudra Periyasamy
  • Terry D Hinds
  • EDWIN R SANCHEZ
  • Weinian Shou
  • Weidong Yong
  • Harrison A Cash
  • Lance A Stechschulte
  • Sonia M Najjar
  • Ananya Banerjee
  • Irene M Wolf
  • Hanying Chen
  • Manya Warrier
  • Saja S Khuder
  • Donald Whisler
  • Meenakshi K Kaw
  • Yuhong Zhou
  • Kelly J Ledford
  • Garrett Heinrich
  • Thomas A Bowman
  • Payal R Patel
  • Zuocheng Yang
  • Sadeesh Ramakrishnan
  • Terry Hinds

Detail Information

Publications8

  1. pmc Protein phosphatase 5
    Terry D Hinds
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, 3035 Arlington Avenue, Toledo, OH 43614 5804, USA
    Int J Biochem Cell Biol 40:2358-62. 2008
    ..Here, we review the signaling involvement of PP5 in light of new findings and relate these activities to the structural features of the protein...
  2. pmc Control of glucocorticoid and progesterone receptor subcellular localization by the ligand-binding domain is mediated by distinct interactions with tetratricopeptide repeat proteins
    Ananya Banerjee
    Department of Physiology and Pharmacology, Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, 3035 Arlington Avenue, Toledo, Ohio 43614 5804, USA
    Biochemistry 47:10471-80. 2008
    ..Our results demonstrate that SRs have distinct preferences for TPR proteins, a property that resides in the LBD and which can now explain long-standing differences in receptor subcellular localization...
  3. pmc Targeted ablation reveals a novel role of FKBP52 in gene-specific regulation of glucocorticoid receptor transcriptional activity
    Irene M Wolf
    Department of Physiology and Pharmacology and the Center for Diabetes and Endocrine Research CeDER, University of Toledo College of Medicine, 3035 Arlington Avenue, Toledo, OH 43614 5804, USA
    J Steroid Biochem Mol Biol 113:36-45. 2009
    ..The implications of these results to the potential actions of FKBP52 on GR activity in vivo are discussed...
  4. pmc FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A
    S Periyasamy
    Center for Diabetes and Endocrine Research CeDER, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614 2598, USA
    Oncogene 29:1691-701. 2010
    ..These proteins and their cognate ligands thus provide new strategies in the treatment of PCa...
  5. pmc Susceptibility to diet-induced hepatic steatosis and glucocorticoid resistance in FK506-binding protein 52-deficient mice
    Manya Warrier
    Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614 5804, USA
    Endocrinology 151:3225-36. 2010
    ..We propose a model in which FKBP52 loss reduces GR control of gluconeogenesis, predisposing the liver to steatosis under HF-diet conditions attributable to a shunting of metabolism from glucose production to lipogenesis...
  6. pmc Fkbp52 regulates androgen receptor transactivation activity and male urethra morphogenesis
    Hanying Chen
    Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Biol Chem 285:27776-84. 2010
    ..Taken together, our data show Fkbp52 to be an important molecular regulator in the androgen-mediated pathway of urethra morphogenesis...
  7. pmc Discovery of glucocorticoid receptor-beta in mice with a role in metabolism
    Terry D Hinds
    Department of Physiology and Pharmacology, University of Toledo College of Medicine, 3035 Arlington Avenue, Toledo, OH 43614 5804, USA
    Mol Endocrinol 24:1715-27. 2010
    ..In mice subjected to fasting-refeeding, a large increase of GRbeta was seen in the liver, whereas mGRalpha was unchanged. This work uncovers the much-needed rodent model of GRbeta for investigations of physiology and disease...
  8. pmc Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ)
    Terry D Hinds
    Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, Ohio 43614, USA
    J Biol Chem 286:42911-22. 2011
    ..This work identifies PP5 as a fulcrum point in nuclear receptor control of the lipolysis/lipogenesis equilibrium and as a potential target in the treatment of obesity...