# Role of HDAC6 in the Regulation of Energy Homeostasis and Leptin Sensitivity

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $394,764

## Abstract

Obesity and overweight affect more than one third of the world population, and are significant risk factors for a
number of comorbidities including cardiovascular disease, cancer and diabetes. Common obesity is usually
accompanied by elevated circulating levels of leptin, the primary adipostatic factor in mammals. Methods
augmenting leptin sensitivity may represent safe and effective means of treating obesity. This proposal
presents compelling new preliminary data showing that peripheral administration of a specific histone
deacetylase 6 (HDAC6) inhibitor (Tubastatin A) to diet-induced obese mice suppresses food intake and
reduces obesity, in an HDAC6-dependent manner, with up to 50 percent decrease in fat mass. These
improvements are accompanied by significantly reduced hepatic steatosis, and improved systemic glucose
homeostasis. Tubastatin does not induce weight loss in leptin receptor mutant db/db mice, or lean wild type
mice, but increases the sensitivity of animals to exogenous leptin administration. Tubastatin-induced metabolic
improvements are independent of central HDAC6 activity, and in large part depends on adipose tissue HDAC6
expression. The current application is centered on the hypothesis that peripheral HDAC6 inhibition confers
central leptin sensitization, and proposes to identify the anatomical (Aim 1) and molecular (Aim 2) mechanisms
of HDAC6 inhibition-mediated amelioration of obesity and diabetes using a combination of genetic,
pharmacological and biochemical approaches. Aim 3 will explore the central mediators of leptin sensitization,
and how blood brain barrier permeability is potentially altered by HDAC6 inhibitors. It will further study the role
of the non-receptor tyrosine kinase Pyk2 as a potentially novel regulator or leptin receptor signaling. This
proposal presents HDAC6 as a novel regulator of energy homeostasis and as a potential target for
development of novel therapeutic approaches against obesity. More generally, this work will establish a
fundamental platform for basic and clinical research for the treatment of obesity and eating disorders.

## Key facts

- **NIH application ID:** 10352472
- **Project number:** 5R01DK125830-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Roger D. Cone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $394,764
- **Award type:** 5
- **Project period:** 2021-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10352472

## Citation

> US National Institutes of Health, RePORTER application 10352472, Role of HDAC6 in the Regulation of Energy Homeostasis and Leptin Sensitivity (5R01DK125830-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10352472. Licensed CC0.

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