Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues

Nature Chemical Biology volume 14, pages 1021–1031 (2018)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mammalian adipocytes synthesize mmBCFAs via fatty acid synthase.
Fig. 2: BCAA catabolic intermediates drive mmBCFA synthesis.
Fig. 3: mmBCFAs are de novo synthesized in vivo.
Fig. 4: BCAA flux to mmBCFAs is decreased by diet-induced obesity.
Fig. 5: Adipose tissue mmBCFA synthesis is facilitated by CrAT.
Fig. 6: Hypoxia suppresses BCAA catabolism and mmBCFA synthesis in adipocytes.

Similar content being viewed by others

Data availability

The data sets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Newgard, C. B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311–326 (2009).

    Article  CAS  Google Scholar 

  2. Wang, T. J. et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17, 448–453 (2011).

    Article  Google Scholar 

  3. Tönjes, M. et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat. Med. 19, 901–908 (2013).

    Article  Google Scholar 

  4. Overmyer, K. A. et al. Maximal oxidative capacity during exercise is associated with skeletal muscle fuel selection and dynamic changes in mitochondrial protein acetylation. Cell Metab. 21, 468–478 (2015).

    Article  CAS  Google Scholar 

  5. Herman, M. A., She, P., Peroni, O. D., Lynch, C. J. & Kahn, B. B. Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J. Biol. Chem. 285, 11348–11356 (2010).

    Article  CAS  Google Scholar 

  6. Crown, S. B., Marze, N. & Antoniewicz, M. R. Catabolism of branched chain amino acids contributes significantly to synthesis of odd-chain and even-chain fatty acids in 3T3-L1 adipocytes. PLoS ONE. 10, e0145850 (2015).

    Article  Google Scholar 

  7. Green, C. R. et al. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat. Chem. Biol. 12, 15–21 (2016).

    Article  CAS  Google Scholar 

  8. Ran-Ressler, R. R., Bae, S., Lawrence, P., Wang, D. H. & Brenna, J. T. Branched-chain fatty acid content of foods and estimated intake in the USA. Br. J. Nutr. 112, 565–572 (2014).

    Article  CAS  Google Scholar 

  9. Jenkins, B., West, J. A. & Koulman, A. A review of odd-chain fatty acid metabolism and the role of pentadecanoic Acid (c15: 0) and heptadecanoic Acid (c17:0) in health and disease. Molecules 20, 2425–2444 (2015).

    Article  Google Scholar 

  10. Mercier, R., Domínguez-Cuevas, P. & Errington, J. Crucial role for membrane fluidity in proliferation of primitive cells. Cell Rep. 1, 417–423 (2012).

    Article  CAS  Google Scholar 

  11. Kniazeva, M., Zhu, H., Sewell, A. K. & Han, M. A lipid-TORC1 pathway promotes neuronal development and foraging behavior under both fed and fasted conditions in C. elegans. Dev. Cell 33, 260–271 (2015).

    Article  CAS  Google Scholar 

  12. Gibson, R. A. & Kneebone, G. M. Fatty acid composition of human colostrum and mature breast milk. Am. J. Clin. Nutr. 34, 252–257 (1981).

    Article  CAS  Google Scholar 

  13. Grigor, M. R., Dunckley, G. G. & Purves, H. D. The synthesis of the branched-chain fatty acids of rat skin surface lipid. Biochim. Biophys. Acta 218, 389–399 (1970).

    Article  CAS  Google Scholar 

  14. Ran-Ressler, R. R., Devapatla, S., Lawrence, P. & Brenna, J. T. Branched chain fatty acids are constituents of the normal healthy newborn gastrointestinal tract. Pediatr. Res. 64, 605–609 (2008).

    Article  CAS  Google Scholar 

  15. Su, X. et al. Adipose tissue monomethyl branched-chain fatty acids and insulin sensitivity: effects of obesity and weight loss. Obesity (Silver Spring) 23, 329–334 (2015).

    Article  CAS  Google Scholar 

  16. Mika, A. et al. A comprehensive study of serum odd- and branched-chain fatty acids in patients with excess weight. Obesity (Silver Spring) 24, 1669–1676 (2016).

    Article  CAS  Google Scholar 

  17. Lackey, D. E. et al. Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. Am. J. Physiol. Endocrinol. Metab. 304, E1175–E1187 (2013).

    Article  CAS  Google Scholar 

  18. Kishimoto, Y., Williams, M., Moser, H. W., Hignite, C. & Biermann, K. Branched-chain and odd-numbered fatty acids and aldehydes in the nervous system of a patient with deranged vitamin B 12 metabolism. J. Lipid Res. 14, 69–77 (1973).

    CAS  PubMed  Google Scholar 

  19. Svensson, R. U. et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat. Med. 22, 1108–1119 (2016).

    Article  CAS  Google Scholar 

  20. Hiltunen, J. K. et al. Mitochondrial fatty acid synthesis type II: more than just fatty acids. J. Biol. Chem. 284, 9011–9015 (2009).

    Article  CAS  Google Scholar 

  21. Lewis, C. A. et al. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol. Cell 55, 253–263 (2014).

    Article  CAS  Google Scholar 

  22. Horning, M. G., Martin, D. B., Karmen, A. & Vagelos, P. R. Fatty acid synthesis in adipose tissue. II. Enzymatic synthesis of branched chain and odd-numbered fatty acids. J. Biol. Chem. 236, 669–672 (1961).

    CAS  PubMed  Google Scholar 

  23. Oku, H., Yagi, N., Nagata, J. & Chinen, I. Precursor role of branched-chain amino acids in the biosynthesis of iso and anteiso fatty acids in rat skin. Biochim. Biophys. Acta 1214, 279–287 (1994).

    Article  Google Scholar 

  24. Liu, L. et al. Human fetal intestinal epithelial cells metabolize and incorporate branched chain fatty acids in a structure specific manner. Prostaglandins Leukot. Essent. Fatty Acids 116, 32–39 (2017).

    Article  CAS  Google Scholar 

  25. Obayashi, M. et al. Estrogen controls branched-chain amino acid catabolism in female rats. J. Nutr. 134, 2628–2633 (2004).

    Article  CAS  Google Scholar 

  26. Kaneda, T. Iso- and anteiso-fatty acids in bacteria: biosynthesis, function, and taxonomic significance. Microbiol. Rev. 55, 288–302 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Macfarlane, G. T., Gibson, G. R., Beatty, E. & Cummings, J. H. Estimation of short-chain fatty acid production from protein by human intestinal bacteria based on branched-chain fatty acid measurements. FEMS Microbiol. Lett. 101, 81–88 (1992).

    Article  CAS  Google Scholar 

  28. Previs, S. F. et al. New methodologies for studying lipid synthesis and turnover: looking backwards to enable moving forwards. Biochim. Biophys. Acta 1842, 402–413 (2014).

    Article  CAS  Google Scholar 

  29. Abdelmagid, S. A. et al. Comprehensive profiling of plasma fatty acid concentrations in young healthy Canadian adults. PLoS ONE. 10, e0116195 (2015).

    Article  Google Scholar 

  30. Sailer, M. et al. Increased plasma citrulline in mice marks diet-induced obesity and may predict the development of the metabolic syndrome. PLoS ONE. 8, e63950 (2013).

    Article  CAS  Google Scholar 

  31. Jenkins, B. J. et al. Odd chain fatty acids; new insights of the relationship between the gut microbiota, dietary intake, biosynthesis and glucose Intolerance. Sci. Rep. 7, 44845 (2017).

    Article  CAS  Google Scholar 

  32. Eissing, L. et al. De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health. Nat. Commun. 4, 1528 (2013).

    Article  Google Scholar 

  33. Duarte, J. A. et al. A high-fat diet suppresses de novo lipogenesis and desaturation but not elongation and triglyceride synthesis in mice. J. Lipid Res. 55, 2541–2553 (2014).

    Article  CAS  Google Scholar 

  34. Sanchez-Gurmaches, J. et al. Brown fat AKT2 is a cold-induced kinase that stimulates ChREBP-mediated de novo lipogenesis to optimize fuel storage and thermogenesis. Cell Metab. 27, 195–209.e6 (2018).

    Article  CAS  Google Scholar 

  35. Violante, S. et al. Substrate specificity of human carnitine acetyltransferase: implications for fatty acid and branched-chain amino acid metabolism. Biochim. Biophys. Acta 1832, 773–779 (2013).

    Article  CAS  Google Scholar 

  36. Geiger, T. et al. Initial quantitative proteomic map of 28 mouse tissues using the SILAC mouse. Mol. Cell. Proteomics. 12, 1709–1722 (2013).

    Article  CAS  Google Scholar 

  37. Trayhurn, P., Wang, B. & Wood, I. S. Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br. J. Nutr. 100, 227–235 (2008).

    Article  CAS  Google Scholar 

  38. Robciuc, M. R. et al. VEGFB/VEGFR1-induced expansion of adipose vasculature counteracts obesity and related metabolic complications. Cell Metab. 23, 712–724 (2016).

    Article  CAS  Google Scholar 

  39. Ye, J., Gao, Z., Yin, J. & He, Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am. J. Physiol. Endocrinol. Metab. 293, E1118–E1128 (2007).

    Article  CAS  Google Scholar 

  40. Mayers, J. R. et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353, 1161–1165 (2016).

    Article  CAS  Google Scholar 

  41. Jang, C. et al. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat. Med. 22, 421–426 (2016).

    Article  CAS  Google Scholar 

  42. Anderson, K. A. et al. SIRT4 Is a lysine deacylase that controls leucine metabolism and insulin secretion. Cell Metab. 25, 838–855.e15 (2017).

    Article  CAS  Google Scholar 

  43. Hellerstein, M. K., Neese, R. A. & Schwarz, J. M. Model for measuring absolute rates of hepatic de novo lipogenesis and reesterification of free fatty acids. Am. J. Physiol. 265, E814–E820 (1993).

    CAS  PubMed  Google Scholar 

  44. Shin, A. C. et al. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metab. 20, 898–909 (2014).

    Article  CAS  Google Scholar 

  45. Seiler, S. E. et al. Carnitine acetyltransferase mitigates metabolic inertia and muscle fatigue during exercise. Cell Metab. 22, 65–76 (2015).

    Article  CAS  Google Scholar 

  46. Davies, M. N. et al. The acetyl group buffering action of carnitine acetyltransferase offsets macronutrient-induced lysine acetylation of mitochondrial proteins. Cell Rep. 14, 243–254 (2016).

    Article  CAS  Google Scholar 

  47. Mardinoglu, A. et al. Integration of clinical data with a genome-scale metabolic model of the human adipocyte. Mol. Syst. Biol. 9, 649 (2013).

    Article  CAS  Google Scholar 

  48. Kniazeva, M., Euler, T. & Han, M. A branched-chain fatty acid is involved in post-embryonic growth control in parallel to the insulin receptor pathway and its biosynthesis is feedback-regulated in C. elegans. Genes Dev. 22, 2102–2110 (2008).

    Article  CAS  Google Scholar 

  49. Yan, Y. et al. BCFA suppresses LPS induced IL-8 mRNA expression in human intestinal epithelial cells. Prostaglandins Leukot. Essent. Fatty Acids 116, 27–31 (2017).

    Article  CAS  Google Scholar 

  50. Ran-Ressler, R. R. et al. Branched chain fatty acids reduce the incidence of necrotizing enterocolitis and alter gastrointestinal microbial ecology in a neonatal rat model. PLoS ONE. 6, e29032 (2011).

    Article  CAS  Google Scholar 

  51. Gantner, M. L., Hazen, B. C., Eury, E., Brown, E. L. & Kralli, A. Complementary roles of estrogen-related receptors in brown adipocyte thermogenic function. Endocrinology 157, 4770–4781 (2016).

    Article  CAS  Google Scholar 

  52. Vacanti, N. M. et al. Regulation of substrate utilization by the mitochondrial pyruvate carrier. Mol. Cell 56, 425–435 (2014).

    Article  CAS  Google Scholar 

  53. Cabrales, P. & Tsai, A. G. Plasma viscosity regulates systemic and microvascular perfusion during acute extreme anemic conditions. Am. J. Physiol. Heart Circ. Physiol. 291, H2445–H2452 (2006).

    Article  CAS  Google Scholar 

  54. Decaris, M. L. et al. Identifying nonalcoholic fatty liver disease patients with active fibrosis by measuring extracellular matrix remodeling rates in tissue and blood. Hepatology 65, 78–88 (2017).

    Article  CAS  Google Scholar 

  55. Fernandez, C. A., Des Rosiers, C., Previs, S. F., David, F. & Brunengraber, H. Correction of 13C mass isotopomer distributions for natural stable isotope abundance. J. Mass. Spectrom. 31, 255–262 (1996).

    Article  CAS  Google Scholar 

  56. Young, J. D. INCA: a computational platform for isotopically non-stationary metabolic flux analysis. Bioinformatics 30, 1333–1335 (2014).

    Google Scholar 

  57. Lee, W. N. et al. In vivo measurement of fatty acids and cholesterol synthesis using D2O and mass isotopomer analysis. Am. J. Physiol. 266, E699–E708 (1994).

    Article  CAS  Google Scholar 

  58. Louie, S. M. et al. GSTP1 Is a driver of triple-negative breast cancer cell metabolism and pathogenicity. Cell Chem. Biol. 23, 567–578 (2016).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

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

    Martina Wallace, Courtney R. Green, Noah Meurs, Jivani M. Gengatharan, Justin D. Hover, Pedro Cabrales & Christian M. Metallo

  2. Departments of Chemistry, Molecular and Cell Biology, and Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA, USA

    Lindsay S. Roberts & Daniel K. Nomura

  3. Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA, USA

    Yujung Michelle Lee, Justin L. McCarville & Janelle S. Ayres

  4. Division of Biological Sciences, University of California at San Diego, La Jolla, CA, USA

    Yujung Michelle Lee

  5. Division of Endocrinology, Division of Developmental Biology, Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH, USA

    Joan Sanchez-Gurmaches

  6. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Joan Sanchez-Gurmaches

  7. Division of Pediatric Endocrinology, Department of Pediatrics, University of California at San Diego, La Jolla, CA, USA

    Susan A. Phillips

  8. Virginia San Diego Healthcare System, San Diego, CA, USA

    Theodore P. Ciaraldi

  9. Division of Endocrinology & Metabolism, Department of Medicine, University of California at San Diego, La Jolla, CA, USA

    Theodore P. Ciaraldi

  10. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    David A. Guertin

  11. NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA, USA

    Rohit Loomba

  12. Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA

    Christian M. Metallo

  13. Diabetes Research Center, University of California, San Diego, La Jolla, CA, USA

    Christian M. Metallo

Authors
  1. Martina Wallace
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Courtney R. Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lindsay S. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yujung Michelle Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Justin L. McCarville
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joan Sanchez-Gurmaches
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Noah Meurs
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jivani M. Gengatharan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Justin D. Hover
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Susan A. Phillips
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Theodore P. Ciaraldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. David A. Guertin
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Pedro Cabrales
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Janelle S. Ayres
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Daniel K. Nomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Rohit Loomba
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Christian M. Metallo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Christian M. Metallo.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Tables and Figures

Supplementary Tables 1–7, Supplementary Figures 1–12

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41589-018-0132-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research