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Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis

Nature Chemical Biology volume 12, pages 15–21 (2016)Cite this article

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Abstract

Adipose tissue plays important roles in regulating carbohydrate and lipid homeostasis, but less is known about the regulation of amino acid metabolism in adipocytes. Here we applied isotope tracing to pre-adipocytes and differentiated adipocytes to quantify the contributions of different substrates to tricarboxylic acid (TCA) metabolism and lipogenesis. In contrast to proliferating cells, which use glucose and glutamine for acetyl–coenzyme A (AcCoA) generation, differentiated adipocytes showed increased branched-chain amino acid (BCAA) catabolic flux such that leucine and isoleucine from medium and/or from protein catabolism accounted for as much as 30% of lipogenic AcCoA pools. Medium cobalamin deficiency caused methylmalonic acid accumulation and odd-chain fatty acid synthesis. Vitamin B12 supplementation reduced these metabolites and altered the balance of substrates entering mitochondria. Finally, inhibition of BCAA catabolism compromised adipogenesis. These results quantitatively highlight the contribution of BCAAs to adipocyte metabolism and suggest that BCAA catabolism has a functional role in adipocyte differentiation.

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Figure 1: Characterization of metabolic reprogramming during adipocyte differentiation.
Figure 2: BCAA catabolism is initiated upon adipocyte differentiation.
Figure 3: BCAA catabolism fuels mitochondrial metabolism and lipogenesis in adipocytes.
Figure 4: BCAA utilization is supported by protein catabolism.
Figure 5: BCAAs contribute to MMA, OCFAs and BCFAs in differentiated 3T3-L1 adipocytes.
Figure 6: Inhibition of BCAA catabolism impairs adipocyte differentiation.

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Acknowledgements

We thank R.R. Henry (R.R.H.; Veterans Affairs San Diego Healthcare System, San Diego, California, USA) for human adipocyte material. This work was supported, in part, by US National Institutes of Health (NIH) grant R01CA188652 (C.M.M.), California Institute of Regenerative Medicine (CIRM) Award RB5-07356 (C.M.M.), US Department of Defense (DOD) grant W81XWH-13-1-0105 (C.M.M.) and a Searle Scholar Award (C.M.M.), as well as grants from the American Diabetes Association (7-05-DCS-04), the Medical Research Service (1 I010X00635-01A1), the US Department of Veterans Affairs and the VA San Diego Healthcare System (R.R.H.), NIH grant 1R01NS087611 (A.N.M.) and a grant from Seahorse Bioscience.

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Authors and Affiliations

  1. Department of Bioengineering, University of California, San Diego, La Jolla, California, USA

    Courtney R Green, Martina Wallace & Christian M Metallo

  2. Department of Pharmacology, University of California, San Diego, La Jolla, California, USA

    Ajit S Divakaruni & Anne N Murphy

  3. Veterans Affairs San Diego Healthcare System, San Diego, California, USA

    Susan A Phillips & Theodore P Ciaraldi

  4. Department of Medicine, University of California, San Diego, La Jolla, California, USA

    Susan A Phillips & Theodore P Ciaraldi

  5. Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California, USA

    Christian M Metallo

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Contributions

S.A.P. and T.P.C. obtained biopsies and isolated human pre-adipocytes from adipose tissue; A.S.D. and A.N.M. performed oxygen consumption experiments; C.R.G. and M.W. performed all other experiments. C.R.G., M.W., A.S.D., A.N.M., T.P.C. and C.M.M. designed research; C.R.G., M.W. and C.M.M. wrote the paper with help from all authors.

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Correspondence to Christian M Metallo.

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Green, C., Wallace, M., Divakaruni, A. et al. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat Chem Biol 12, 15–21 (2016). https://doi.org/10.1038/nchembio.1961

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