Publication Date
8-1-2024
Journal
Molecular Metabolism
DOI
10.1016/j.molmet.2024.101983
PMID
38960128
PMCID
PMC11292358
PubMedCentral® Posted Date
7-1-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Insulin Resistance, Mice, Obesity, Mice, Knockout, Muscle, Skeletal, Adipocytes, Male, Mice, Inbred C57BL, Mitochondriam, Mitochondria, Adipose tissue, Insulin resistance, Peptidases, Metabolism, Skeletal muscle
Abstract
Mitochondria facilitate thousands of biochemical reactions, covering a broad spectrum of anabolic and catabolic processes. Here we demonstrate that the adipocyte mitochondrial proteome is markedly altered across multiple models of insulin resistance and reveal a consistent decrease in the level of the mitochondrial processing peptidase miPEP.
OBJECTIVE: To determine the role of miPEP in insulin resistance.
METHODS: To experimentally test this observation, we generated adipocyte-specific miPEP knockout mice to interrogate its role in the aetiology of insulin resistance.
RESULTS: We observed a strong phenotype characterised by enhanced insulin sensitivity and reduced adiposity, despite normal food intake and physical activity. Strikingly, these phenotypes vanished when mice were housed at thermoneutrality, suggesting that metabolic protection conferred by miPEP deletion hinges upon a thermoregulatory process. Tissue specific analysis of miPEP deficient mice revealed an increment in muscle metabolism, and upregulation of the protein FBP2 that is involved in ATP hydrolysis in the gluconeogenic pathway.
CONCLUSION: These findings suggest that miPEP deletion initiates a compensatory increase in skeletal muscle metabolism acting as a protective mechanism against diet-induced obesity and insulin resistance.
Graphical Abstract
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Biochemical Phenomena, Metabolism, and Nutrition Commons, Biology Commons, Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Musculoskeletal Diseases Commons
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