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

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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.