# Molecular regulation of leptin bioavailability

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $657,578

## Abstract

ABSTRACT
The obesity epidemic contributes to the increased health burden of chronic inflammatory conditions, including
insulin resistance, type 2 diabetes mellitus (T2DM), fatty liver, and cardiovascular disease. New strategies for
prevention and treatment are crucial to improve the quality of life for people with obesity and T2DM, especially
given that behavioral and lifestyle modifications are ineffective alternatives for most of the affected population.
Our long-term objective is to identify safe treatments for obesity and T2DM that can restore the normal endocrine
functions of insulin-resistant fat cells. Working towards this objective, we found the FDA-approved rheumatoid
arthritis drug auranofin generates anti-diabetic effects. We have robust preliminary data showing auranofin
accumulation in WAT reduces leptin abundance in the serum and generates whole-body insulin sensitivity in
obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved
by leptin receptor deletion abolished the anti-diabetic effects of auranofin. This application will build upon our
preliminary data and test the hypothesis that impacts of auranofin accumulation in WAT restore beta-adrenergic
receptor competence to limit leptin production and benefit systemic metabolism in obesity. The overall goal of
this application is to explore how auranofin influences insulin sensitivity in preclinical models of obesity with the
expectation that its effects require the vital endocrine hormone leptin. To achieve our overall goal and test the
central hypothesis of the proposal, we propose three specific aims. First, we will demonstrate how the leptin
receptor in WAT influences the metabolic impacts of auranofin. Second, we will establish the serum leptin
decrement required for the anti-diabetic effects of auranofin. Lastly, we will determine the functional role of
adipocyte-intrinsic beta-adrenergic receptors that govern the energy balance impacts of auranofin. Ultimately,
such knowledge will teach us how to leverage the endocrine functions of WAT to treat obesity and its co-
morbidities. Completion of this proposal will tell us how to leverage new pathways that generate metabolic
benefits in preclinical models of obesity and potentially allow people accessible therapeutic options to manage
insulin resistance and T2DM.

## Key facts

- **NIH application ID:** 10779215
- **Project number:** 1R01DK138018-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Sean Hartig
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $657,578
- **Award type:** 1
- **Project period:** 2024-03-20 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10779215

## Citation

> US National Institutes of Health, RePORTER application 10779215, Molecular regulation of leptin bioavailability (1R01DK138018-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10779215. Licensed CC0.

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