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OPA1 Regulates Lipid Metabolism and Cold-Induced Browning of White Adipose Tissue in Mice

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posted on 2022-09-28, 20:37 authored by Renata O. Pereira, Angela C. Olvera, Alex Marti, Shi Fang, Jeffrey R. White, Michael Westphal, Rana Hewezi, Salma T. AshShareef, Luis Miguel Garcia Pena, Jivan Koneru, Matthew J. Potthoff, E. Dale Abel

Mitochondria play a vital role in white adipose tissue homeostasis including adipogenesis, fatty acid synthesis, and lipolysis. We recently reported that the mitochondrial fusion protein optic atrophy 1 (OPA1) is required for induction of fatty acid oxidation and thermogenic activation in brown adipocytes. The present study investigated the role of OPA1 in white adipose tissue (WAT) function in vivo. We generated mice with constitutive or inducible knockout of OPA1 selectively in adipocytes. Studies were conducted under baseline conditions, at thermoneutrality, following high-fat feeding or during cold exposure. OPA1 deficiency reduced mitochondrial respiratory capacity in white adipocytes, impaired lipolytic signaling, repressed expression of de novo lipogenesis and triglyceride synthesis pathways and promoted adipose tissue senescence and inflammation. Reduced WAT mass was associated with hepatic triglycerides accumulation and glucose intolerance. Moreover, mice deficient for OPA1 in adipocytes had impaired adaptive thermogenesis, reduced cold-induced browning of sub-cutaneous WAT, and were completely resistant to diet-induced obesity. In conclusion, OPA1 expression and function in adipocytes is essential for adipose tissue expansion, lipid biosynthesis and fatty acid mobilization of WAT and brown adipocytes, and for thermogenic activation of brown and beige adipocytes. 

Funding

This work was supported by NIH grants HL127764 and HL112413 and the Teresa Benoit Diabetes research fund to E.D.A., who is an established investigator of the American Heart Association (AHA), and by AHA Scientist Development Grant 15SDG25710438 (to R.O.P.).

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