Abstract
Fatty acid synthase (FASN) predominantly generates straight-chain fatty acids using acetyl-CoA as the initiating substrate. However, monomethyl branched-chain fatty acids (mmBCFAs) are also present in mammals but are thought to be primarily diet derived. Here we demonstrate that mmBCFAs are de novo synthesized via mitochondrial BCAA catabolism, exported to the cytosol by adipose-specific expression of carnitine acetyltransferase (CrAT), and elongated by FASN. Brown fat exhibits the highest BCAA catabolic and mmBCFA synthesis fluxes, whereas these lipids are largely absent from liver and brain. mmBCFA synthesis is also sustained in the absence of microbiota. We identify hypoxia as a potent suppressor of BCAA catabolism that decreases mmBCFA synthesis in obese adipose tissue, such that mmBCFAs are significantly decreased in obese animals. These results identify adipose tissue mmBCFA synthesis as a novel link between BCAA metabolism and lipogenesis, highlighting roles for CrAT and FASN promiscuity influencing acyl-chain diversity in the lipidome.
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The data sets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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Acknowledgements
This work was supported, in part, by US National Institutes of Health (NIH) grants R01CA188652 (C.M.M.), NIH R01CA172667 (D.K.N.), P01-HL110900 (P.C.) and R01-HL126945 (P.C.), a Searle Scholar Award (C.M.M.), a Camille and Henry Dreyfus Teacher-Scholar Award (C.M.M.), an NSF CAREER Award (#1454425 to C.M.M.), and an Ajinomoto Innovation Alliance Program Grant (C.M.M). The project was funded (in part) by a seed grant made available through the UC San Diego Larsson-Rosenquist Foundation Mother-Milk-Infant Center of Research Excellence (M.W). J.S.G. is supported by AHA award 18CDA34080527. This material is the result of work supported with resources and the use of facilities at the VA San Diego Medical Center. The contents do not represent the views of the US Department of Veterans Affairs or the United States Government. We would like to thank M. Gantner for helping with primary brown adipose tissue isolation and culture.
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M.W. and C.M.M. conceived and designed the study. C.R.G. carried out knock down and analysis of ACAD enzymes and assisted with design and execution of all 3T3L1 experiments; L.S.R. and D.K.N. carried out lipidomic analysis of 13C-traced adipocytes; and J.L.M., Y.M.L. and J.S.A. provided germ-free and SPF samples. T.P.C. and S.A.P. isolated and cultured human primary cells. N.M. and J.M.G. assisted with GC–MS analysis of in vivo samples; J.D.H. carried out gene expression analysis of tissue samples, J.S.G. and D.A.G. carried out D2O thermovariation experiments in mice. P.C. carried out in vivo oxygen tension and arterial blood flow studies in mice. M.W. performed all other experiments. R.L. designed and executed the clinical study of NAFL and NASH patients. M.W. and C.M.M. wrote the paper with help from all authors.
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Wallace, M., Green, C.R., Roberts, L.S. et al. Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues. Nat Chem Biol 14, 1021–1031 (2018). https://doi.org/10.1038/s41589-018-0132-2
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DOI: https://doi.org/10.1038/s41589-018-0132-2
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