# Nuclear Receptor Chaperones in Signalingand Metabolism

> **NIH NIH R01** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 2020 · $386,000

## Abstract

Obesity is a hyperlipidemic state characterized by excessive adipose tissue that often leads to diabetes and
osteoporosis. Glucocorticoid receptor-α (GRα) and peroxisome proliferator-activated receptor-γ (PPARγ) are
members of the nuclear receptor family that are essential to adipocyte differentiation and function. In general,
GRα and PPAR-γ can be viewed as physiologic antagonists, with GR promoting lipolysis at adipose tissue, but
PPAR-γ promoting adipogenesis and lipid storage. Moreover, each receptor is regulated by phosphorylation,
but in opposite ways: stimulatory to GRα, but inhibitory to PPAR-γ. We have recently shown that two nuclear
receptor chaperones, protein phosphatase 5 (PP5) and the FK506-binding protein-51 (FKBP51), can
reciprocally regulate the molecular and metabolic activities of GRα and PPAR-γ through phosphorylation. PP5
dephosphorylates GR at multiple serines to decrease its lipolytic activity, while dephosphorylating PPARγ at
serine 112 to increase its adipogenic and lipid storage actions. Thus, PP5 can be viewed as a pro-lipogenic,
anti-lipolytic factor. Our studies in PP5-KO mice support this view since the mice have greatly reduced whole
body fat, including low lipid content in marrow fat cells and increased bone density. Interestingly, the PP5-KO
mice also have increased insulin sensitivity and energy expenditure. The latter features suggest increased
PPARγ insulin-sensitizing activity in the null mice – actions known to be inhibited by CDK5-mediated
phosphorylation at S273 of the receptor. Our latest data suggest that PP5 increases PPARγ S273
phosphorylation by dephosphorylating and activating the p35 regulatory subunit of CDK5. Thus, PP5 may
inversely control the lipogenic and insulin sensitizing actions of PPARγ by directly dephosphorylating the
receptor at S112 and indirectly phosphorylating the receptor at S273 by activating CDK5. We have shown that
FKBP51 also negatively regulates GRα and positively regulates PPARγ, but it does so by inhibiting the Akt-p38
kinase pathway, leading to decreased phosphorylation of PPARγ at S112 and GRα at serines 220 and 234.
This results in FKBP51-KO cells that are also resistant to adipogenesis and lipid buildup and in FKBP51-KO
mice with reduced adipose depots and increased bone mass. Interestingly, FKBP51-KO mice are resistant to
high-fat diet effects on insulin sensitivity and resistant to the PPAR-γ agonist rosiglitazone. In this application,
we will test the overall hypothesis that PP5 and FKBP51 are pro-adipogenic, pro-osteoporotic and pro-diabetic
factors that act in adipose tissue by differentially targeting GRα and PPAR-γ via phosphorylation. Thus, each
chaperone may represents a new potential drug target for obesity, osteoporosis and diabetes through the dual
effect of inhibiting lipogenesis/osteoporosis but promoting anti-diabetics activities. This will be tested in
molecular and cellular assays to further define the roles of the CDK5 and Akt-p38 kinase pathways in
regu...

## Key facts

- **NIH application ID:** 9970493
- **Project number:** 5R01DK121017-02
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **Principal Investigator:** EDWIN RAMON SANCHEZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,000
- **Award type:** 5
- **Project period:** 2019-07-02 → 2022-04-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970493

## Citation

> US National Institutes of Health, RePORTER application 9970493, Nuclear Receptor Chaperones in Signalingand Metabolism (5R01DK121017-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9970493. Licensed CC0.

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