Prohibitin-1 cysteine-69 plays a sex-dependent role in fatty acid metabolism.

Metabolic diseases are caused by dysregulation of glucose and lipid homeostasis, which relies on the function of adipose tissues. This regulation and the associated pathologies differ between sexes, which remain incompletely understood. Prohibitin-1 (PHB1) has multifaceted tissue-specific functions converging on metabolism. Here, we investigated the role of PHB1's evolutionarily conserved cysteine-69 by replacing it with an alanine in a knock-in (Phb1-KI) mouse model. We show that Phb1-KI mice lack cell surface localization of PHB1 and display sex-biased adipose tissue alterations in relative sizes of visceral and subcutaneous depots and their adipocyte sizes, expression of lipid metabolism effectors, and adipokine secretion. Phb1-KI adipocytes are defective in long-chain fatty acid uptake and mobilization, and their mitochondrial abnormalities and reduced oxidative capacity result in defective lipid metabolism. In compensation, Phb1-KI have increased glycolysis and Phb1-KI mice display improved glucose disposal and increased insulin sensitivity. Attributes of this phenotype manifested differently in males and females of Phb1-KI mice. Our results demonstrate the importance of cysteine-69 in sex-related function of PHB1 in integrative physiology and systemic metabolism.