# Therapeutic strategies to induce browning of white adipose tissue

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $412,500

## Abstract

SUMMARY
Obesity has reached pandemic proportions contributing to the development of the metabolic syndrome, a
group of disorders that include type 2-diabetes and cardiovascular disease. The obesity epidemic is
increasing at an alarming rate and new therapies are needed. Lifestyle modifications alone, such as diet
and exercise, are not sufficient to combat these diseases. Excess caloric intake causes the rapid expansion
of adipocytes leading to lipotoxic side effects, including ectopic fat accumulation and insulin resistance.
Obese white adipose tissue (WAT) undergoes substantial remodeling which includes infiltration of
macrophages and fibrosis. Remodeling of WAT can also be beneficial and coincide with conditions that
enhance insulin sensitivity and reduce inflammation. Exposure of mice to the cold or treating them with
various pharmacological agents such as PPARγ agonists induce browning of WAT, which include
recruitment of brown-like adipocytes referred to as beige and brite cells. Besides supplying the depot with
thermogenic cells, browning has the potential to remodel obese WAT in ways associated with a lean
phenotype including secretion of “healthy” adipokines. It is our suggestion that identifying novel pathways
and strategies to safely and specifically activate PPARγ is perhaps the most efficacious way to induce
beige/brite adipocytes. Millions of individuals already take PPARγ ligands (Avandia and Actos) to treat their
obesity-related insulin resistance. It is well accepted that the principal site of action of these TZDs is
adipose tissue. Even though the TZDs are very effective and potent insulin sensitizers they are fraught with
harmful side effects. Studies by others and us have shown that targeting specific posttranslational
modifications of PPARγ is a means to circumvent the harmful effects of PPARγ agonists while retaining the
insulin sensitizing activity. Our recent study on which this proposal is based demonstrated that roscovitine, a
CDK inhibitor potently browned WAT and protected mice from diet-induced obesity (DIO) and insulin
resistance. We hypothesize that roscovotine browns WAT through post-translational modifications of
PPARγ and in doing so overcomes the harmful effects of obesity. We propose four aims to test this
hypothesis: 1. Trace the origin of beige/brite adipocytes induced by treatment of mice with roscovitine. 2.
Determine whether roscovitine prevents obesity-induced expansion and activation of myofibroblasts. 3.
Identify and characterize the co-regulators (coactivators and corepressors) interacting with a
phosphorylation (S112A/S273A) deficient form of PPARγ in adipocytes in mice. 4. Determine whether
expression of the modified PPARγ in adipose depots induces browning of WAT and protects against diet-
induced obesity and fibrosis. Successful completion of these aims will provide novel insights into pathways
regulating beige/brite AT formation, thus advancing our understanding of how to therapeutically target
adi...

## Key facts

- **NIH application ID:** 10146358
- **Project number:** 5R01DK117163-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** STEPHEN ROBERT FARMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $412,500
- **Award type:** 5
- **Project period:** 2019-07-19 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146358

## Citation

> US National Institutes of Health, RePORTER application 10146358, Therapeutic strategies to induce browning of white adipose tissue (5R01DK117163-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10146358. Licensed CC0.

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