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Principal Investigator: Ling Yang
Organization: UNIVERSITY OF IOWA
Fiscal Year: 2024
Award: $473,076
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <Active Oxygen><Adipose tissue><Adrenergic Agents><Adrenergic Drugs><Adrenergics><Aging><Alcohol dehydrogenase><Alcohol-NAD+ Oxidoreductase><Animal Model><Animal Models and Related Studies><Autoregulation><BAT uncoupling protein><Basal Transcription Factor><Basal transcription factor genes><Body Tissues><Brown Adipose Tissue><Brown Fat><Cardiovascular Diseases><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cellular Function><Cellular Physiology><Cellular Process><Chronic><Cofactor Protein S><Cues><Cysteine><Data><Defect><Dehydrogenases><Disease><Disorder><Down-Regulation><Dysfunction><Endogenous Nitrate Vasodilator><Endothelium-Derived Nitric Oxide><Equilibrium><Exposure to><Fatty Tissue><Functional disorder><General Transcription Factor Gene><General Transcription Factors><Glucose Intolerance><Goals><Half-Cystine><Health><Heat Production><Hibernating Gland><Homeostasis><Human><Immune><Immune infiltrates><Immunes><Impairment><Inflammation><Inflammatory><Intermediary Metabolism><Intracellular Communication and Signaling><KO mice><Knock-out Mice><Knockout Mice><Knowledge><L-Cysteine><Laboratory Research><Link><Liver><Mammalia><Mammals><Mediating><Mediator><Mercaptans><Mercapto Compounds><Metabolic><Metabolic Processes><Metabolic dysfunction><Metabolic stress><Metabolism><Mice><Mice Mammals><Mission><Mitochondria><Mitochondrial Proteins><Modern Man><Molecular><Mononitrogen Monoxide><Murine><Mus><NIH><Names><National Institutes of Health><Nitric Oxide><Nitrogen Monoxide><Nitrogen Protoxide><Null Mouse><Nutrient><Obesity><Outcome><Overnutrition><Oxidation-Reduction><Oxidoreductase><Oxidoreductase Gene><Oxygen Radicals><Pathogenesis><Physiological Homeostasis><Physiology><Physiopathology><Play><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Pro-Oxidants><Production><Protein Modification><Protein S><Proteins><Proteomics><Public Health><Reactive Nitrogen Species><Reactive Oxygen Species><Redox><Reductases><Regulation><Research><Respiration><Role><S-Nitroso-GSH><S-Nitrosoglutathione><SKIL><SKIL gene><SNO><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Muscle><Stimulus><Stress><Subcellular Process><Sulfhydryl Compounds><Testing><Therapeutic><Thermogenesis><Thiols><Tissues><Transcription Factor Proto-Oncogene><Transcription factor genes><United States National Institutes of Health><Vitamin K-Dependent Protein S><Voluntary Muscle><adipose><adiposity><balance><balance function><biological adaptation to stress><biological signal transduction><brown adipose tissue uncoupling protein><cardiovascular disorder><corpulence><diet-associated obesity><diet-induced obesity><diet-related obesity><disability><endothelial cell derived relaxing factor><feeding><heat-shock factor 1><hepatic body system><hepatic organ system><human disease><human model><immune cell infiltrate><improved><insight><mitochondrial><model of animal><model of human><name><named><naming><nitrosative stress><novel><oxidation><oxidation reduction reaction><pathophysiology><pharmacologic><protein homeostasis><proteostasis><reaction; crisis><respiratory mechanism><response><restoration><social role><stress response><stress; reaction><stressor><sulfhydryl group><therapeutic target><thermogenin><transcription factor><uncoupling protein 1><white adipose tissue><yellow adipose tissue>