Dataset Information

Deletion of the mitochondrial peptidase miPEP in adipose tissue protects against obesity and insulin resistance by increasing adaptive thermogenesis

ABSTRACT: Mitochondria are pivotal for cellular metabolism, serving as sources and targets of nutrient intermediates from converging metabolic pathways. Here, we demonstrate that insulin resistance leads to a marked alteration in the mitochondrial proteome of adipocytes. Analysis across multiple insulin resistance models revealed a consistent decrease in the level of the mitochondrial processing peptidase miPEP, suggesting a potential role for miPEP in the aetiology of insulin resistance. Adipocyte specific miPEP knockout mice demonstrated a strong phenotype marked by a browning-independent increment in energy expenditure, enhanced insulin sensitivity, and reduced adiposity, despite normal food intake and physical activity. These phenotypes vanished when mice were housed at thermoneutrality suggesting that miPEP deletion triggers a compensatory enhancement in thermogenesis protecting against metabolic dysfunction. Tissue specific analysis of miPEP deficient mice revealed a selective increment in muscle metabolism evidenced by increased basal and insulin induced glucose uptake and upregulation of the protein Fbp2, involved in energy wasting via futile cycling. These findings suggest that miPEP deletion initiates a compensatory increase in thermogenesis, acting as a protective mechanism against diet-induced insulin resistance.

INSTRUMENT(S): Q Exactive HF-X, Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Soleus, Blood Plasma, Adipose Tissue

SUBMITTER: David James

LAB HEAD: Professor David James

PROVIDER: PXD051606 | Pride | 2024-08-10

REPOSITORIES: Pride

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			Action	DRS
	20230717_Exploris480_DH_AD_Mitopep_Brown_126_KO.raw	Raw
	20230717_Exploris480_DH_AD_Mitopep_Brown_127_KO.raw	Raw
	20230717_Exploris480_DH_AD_Mitopep_Brown_128_KO.raw	Raw
	20230717_Exploris480_DH_AD_Mitopep_Brown_129_KO.raw	Raw
	20230717_Exploris480_DH_AD_Mitopep_Brown_132_WT.raw	Raw

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Publications

Deletion of miPEP in adipocytes protects against obesity and insulin resistance by boosting muscle metabolism.

Diaz-Vegas Alexis A Cooke Kristen C KC Cutler Harry B HB Yau Belinda B Masson Stewart W C SWC Harney Dylan D Fuller Oliver K OK Potter Meg M Madsen Søren S Craw Niamh R NR Zhang Yiju Y Moreno Cesar L CL Kebede Melkam A MA Neely G Gregory GG Stöckli Jacqueline J Burchfield James G JG James David E DE

Molecular metabolism 20240701

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.<h4>Objective</h4>To determine the role of miPEP in insulin resistance.<h4>Methods</h4>To experimentally test this observation, we generated adipocyte-speci ...[more]

PMID: 38960128

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