Peroxisomal metabolism of branched fatty acids regulates energy homeostasis
Xuejing Liu, Anyuan He, Dongliang Lu, Donghua Hu, Min Tan, Abenezer Abere, Parniyan Goodarzi, Bilal Ahmad, Brian Kleiboeker, Brian N. Finck, Mohamed A. Zayed, Katsuhiko Funai, Jonathan R. Brestoff, Ali Javaheri, Patricia B. Weisensee, Bettina Mittendorfer, Fong‐Fu Hsu, Paul P. Van Veldhoven, Babak Razani, Clay F. Semenkovich, Irfan J. Lodhi
Abstract
Brown and beige adipocytes express uncoupling protein 1 (UCP1), a mitochondrial protein that dissociates respiration from ATP synthesis and promotes heat production and energy expenditure. However, UCP1−/− mice are not obese1–5, consistent with the existence of alternative mechanisms of thermogenesis6–8. Here we describe a UCP1-independent mechanism of thermogenesis involving ATP-consuming metabolism of monomethyl branched-chain fatty acids (mmBCFA) in peroxisomes. These fatty acids are synthesized by fatty acid synthase using precursors derived from catabolism of branched-chain amino acids9 and our results indicate that β-oxidation of mmBCFAs is mediated by the peroxisomal protein acyl-CoA oxidase 2 (ACOX2). Notably, cold exposure upregulated proteins involved in both biosynthesis and β-oxidation of mmBCFA in thermogenic fat. Acute thermogenic stimuli promoted translocation of fatty acid synthase to peroxisomes. Brown-adipose-tissue-specific fatty acid synthase knockout decreased cold tolerance. Adipose-specific ACOX2 knockout also impaired cold tolerance and promoted diet-induced obesity and insulin resistance. Conversely, ACOX2 overexpression in adipose tissue enhanced thermogenesis independently of UCP1 and improved metabolic homeostasis. Using a peroxisome-localized temperature sensor named Pexo-TEMP, we found that ACOX2-mediated fatty acid β-oxidation raised intracellular temperature in brown adipocytes. These results identify a previously unrecognized role for peroxisomes in adipose tissue thermogenesis characterized by an mmBCFA synthesis and catabolism cycle. A UCP1-independent mechanism of thermogenesis involving ATP-consuming metabolism of monomethyl branched-chain fatty acids in peroxisomes is described and a previously unrecognized role for peroxisomes in adipose tissue thermogenesis is identified.