# Role of ADH5 in the Regulation of Brown Adipose Tissue Metabolic Homeostasis

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2022 · $502,125

## Abstract

PROJECT SUMMARY
Dysregulated metabolic function and chronic inflammation are prominent features of obesity in both humans and
animal models. Brown adipose tissue (BAT) plays a critical role in metabolic adaptation in response to stresses
including overnutrition, wherein the metabolic adaptation is disrupted and inflammatory stress is elevated.
However, there remains a key knowledge gap in the interplay between inflammatory and metabolic cues in BAT
during overnutrition. Obesity-associated chronic inflammation is characterized by excessive nitric oxide (NO)
production and aberrant protein cysteine nitrosylation (S-nitrosylation). Our preliminary data showed that diet-
induced obesity (DIO) elevates BAT protein S-nitrosylation, including uncoupling protein 1 (UCP1). This aberrant
BAT NO bioactivity is in part due to downregulation of alcohol dehydrogenase 5 (ADH5), the major denitrosylase
modulating cellular nitro-thio redox balance. Moreover, we showed that BAT Adh5 deletion suppressed UCP1-
dependent mitochondrial respiration, worsened glucose intolerance and increased BAT inflammation in mice
with DIO. All of these defects were improved by restoration of Adh5 expression in the BAT. These data provide
the first evidence that ADH5 plays a protective role in the BAT against metabolic stress. Thus, we hypothesize
obesity compromises ADH5-regulated cellular nitrosative homeostasis in the thermogenic adipose tissue,
contributing to obesity-associated metabolic dysfunction. We will test this hypothesis by completing two specific
aims. In Aim 1, we will define the mechanism by which obesity suppresses ADH5 expression and its
pathophysiological significance in obesity. In Aim 2, we will determine the molecular mechanisms underlying
ADH5-mediated BAT metabolic homeostasis. The regulation of BAT metabolic function by nitro-redox signaling
and the contribution of this regulation to metabolic dysfunction in obesity are new and unexplored concepts.
Accomplishment of this project will provide first insights into the mechanisms by which aberrant NO signaling
links BAT inflammatory cues to metabolic dysfunction and new avenues for developing of therapeutic targets to
ameliorate BAT dysfunction in the context of obesity.

## Key facts

- **NIH application ID:** 10519684
- **Project number:** 1R01DK126817-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Ling Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $502,125
- **Award type:** 1
- **Project period:** 2022-08-19 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10519684

## Citation

> US National Institutes of Health, RePORTER application 10519684, Role of ADH5 in the Regulation of Brown Adipose Tissue Metabolic Homeostasis (1R01DK126817-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10519684. Licensed CC0.

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