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Branched-Chain Amino Acid Catabolism Fuels Adipocyte Differentiation and Lipogenesis

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Branched-Chain Amino Acid Catabolism Fuels Adipocyte Differentiation and Lipogenesis UC San Diego UC San Diego Previously Published Works Title Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis Permalink https://escholarship.org/uc/item/5hd6t56w Journal Nature Chemical Biology, 12(1) ISSN 1552-4450 Authors Green, CR Wallace, M Divakaruni, AS et al. Publication Date 2016 DOI 10.1038/nchembio.1961 Peer reviewed eScholarship.org Powered by the California Digital Library University of California ARTICLE PUbliShED oNliNE: 16 NoVEmbER 2015 | Doi: 10.1038/NchEmbio.1961 Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis Courtney R Green1, Martina Wallace1, Ajit S Divakaruni2, Susan A Phillips3,4, Anne N Murphy2, Theodore P Ciaraldi3,4 & Christian M Metallo1,5* 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 prolif- erating 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 bal- ance 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. dipose tissue has a major role in glucose and lipid homeo- BCAA levels, transplantation of wild-type adipose tissue to Bcat2−/− stasis via the storage of excess nutrients in lipid droplets mice normalizes plasma BCAAs16–18. Finally, treatment of human Aand the release of bioenergetic substrates through lipolysis. subjects and animals with thiazolidinediones (TZDs), clinically Adipocytes, the major cellular constituent of adipose tissue, execute used activators of peroxisome proliferator-activated receptor-γ important regulatory functions through endocrine and paracrine (PPARγ), increases the transcription of BCAA catabolic genes in signaling1. For example, the synthesis and release of lipids and adipose tissue19,20, suggesting that this metabolic activity may have adipokines influence fatty acid metabolism in the liver, appetite, beneficial effects in the context of T2DM. inflammation and insulin sensitivity2–4. Dysfunction in these path- To date, the extent to which oxidation of BCAAs, relative to ways can contribute to insulin resistance5. Beyond these signaling other substrates, contributes to anaplerosis and DNL has not functions, the increased adiposity associated with obesity and type 2 been quantitatively determined in adipocytes. Here we employed diabetes mellitus (T2DM) highlights the need to better understand 13C-labeled isotope tracers, mass spectrometry and isotopomer Nature America, Inc. All rights reserved. Inc. Nature America, metabolic regulation and activity in adipocytes. spectral analysis (ISA) to quantify BCAA utilization in proliferating 5 Insulin stimulates glucose utilization and de novo lipogenesis pre-adipocytes and differentiated adipocytes. Whereas proliferat- (DNL) in the liver and adipose tissue, and glucose and fatty acids ing pre-adipocytes did not appreciably catabolize these substrates, © 201 are considered the primary carbon sources fueling anaplerosis and BCAAs accounted for as much as one-third of the mitochondrial AcCoA generation in these sites6. Beyond carbohydrates and fat, AcCoA in terminally differentiated 3T3-L1 adipocytes as well as in both essential and nonessential amino acids also contribute signifi- adipocytes isolated from human subcutaneous and visceral adipose cantly to AcCoA metabolism in cells. The branched-chain amino tissues. Furthermore, inadequate cobalamin availability in 3T3-L1 acids (BCAAs) leucine, isoleucine, and valine are important keto- cultures perturbed BCAA and fatty acid metabolism and led to genic and/or anaplerotic substrates in a number of tissues7,8. In fact, the non-physiological accumulation of methylmalonate (MMA) clinical metabolomics studies have recently suggested that plasma and synthesis of odd-chain fatty acids (OCFAs). Finally, inhibition levels of BCAAs, their downstream catabolites (such as acylcarniti- of BCAA catabolism negatively influenced 3T3-L1 adipogenesis. nes) and other essential amino acids become elevated in the context These results highlight the complex interplay between cellular of insulin resistance9–11. However, the mechanisms leading to these differentiation and metabolic pathway flux in adipocyte biology. changes and their ultimate consequences in the context of metabolic syndrome are not fully understood. RESULTS Several past studies provide evidence that adipose tissue plays Adipogenesis reprograms amino acid metabolism a role in BCAA homeostasis, though the quantitative contribution To understand how mitochondrial substrate utilization changes of these amino acids to TCA metabolism relative to those of other during adipogenesis, we quantified the sources of lipogenic AcCoA nutrients is not well defined. Enzyme activity, substrate oxidation before and after differentiation. 3T3-L1 adipocytes displayed sub- and systems-based profiling of 3T3-L1 metabolism suggest that stantial lipid accumulation 7 d after induction of differentiation BCAA consumption increases precipitously during differentiation (Supplementary Results, Supplementary Fig. 1a). Palmitate (total to adipocytes12–14. In addition, the transcription of BCAA catabolic from saponified nonpolar extracts) in proliferating and differenti- 15 13 enzymes increases significantly during 3T3-L1 differentiation . ated 3T3-L1 cells cultured with [U- C6]glucose (Supplementary Whereas genetic modulation of Bcat2 in mice alters circulating Fig. 1b) had the expected pattern of labeling arising via pyruvate 1Department of Bioengineering, University of California, San Diego, La Jolla, California, USA. 2Department of Pharmacology, University of California, San Diego, La Jolla, California, USA. 3Veterans Affairs San Diego Healthcare System, San Diego, California, USA. 4Department of Medicine, University of California, San Diego, La Jolla, California, USA. 5Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California, USA. *e-mail: [email protected] NATURE CHEMICAL BIOLOGY | ADVaNCE ONLINE PUBLICaTION | www.nature.com/naturechemicalbiology 1 ARTICLE Nature chemical biOlOGY Doi: 10.1038/NchEmbio.1961 a Other b c a b 13 100 [U- C5]Glutamine Pre-adipocytes Pre-adipocytes 13 13 [U- C6]Leucine [U- C6]Glucose Adipocytes Adipocytes 90 13 L-Valine L-Isoleucine L-Leucine [U- C6]Isoleucine 100 4 80 ** 80 10 80 *** 3 60 Bckdh Bckdh Bckdh CO CO CO 60 * 2 2 2 5 ]glucose (%) CO 2 6 40 2 mg protein) / *** C Citrate labeling from 40 h CO / ** 13 2 AcCoA *** PropCoA AcCoA 0 Contribution to 1 20 mol indicated tracer substrate (%) 20 Total enrichment PropCoA µ ( lipogenic AcCoA (%) M0 M1 M2 M3 M4 M5 M6 from [U- 0 Uptake and secretion fluxes 0 0 Number of isotopes per molecule 143B Serine A549HuH-7 Glycine SAT pre-adipocytes c d ) Glutamine 80 10 SAT adipocytes Glucose uptake Lactate secretion OAT pre-adipocytes 3T3-L1 adipocytes Glutamine uptake *** m 8 Glutamate secretion 60 OAT adipocytes 3T3-L1 pre-adipocytes Pre-adipocytes 6 * ** * d Pre-adipocytes e [15N]Leucine 40 Adipocytes 250 60 15 4 n Adipocytes *** [ N]Valine ) [15N]BCAAs 20 Citrate MPE from 200 Citrate MPE fro 2 40 150 0 indicated tracer substrate (%) 0 *** indicated tracer substrate (% *** 100 *** *** 20 ]Glucose ]Leucine 6 ]Leucine 6 ]Glutamine13 C ]Isoleucine 6 50 13 C 13 C ]Isoleucine 5 C 6 6 13 C 13 13 C specified tracers (% M1 label on AAs from [U- [U- [U- AA uptake and secretio 0 0 [U- [U- [U- fluxes (nmol/h/mg protein) Valine Serine Serine Leucine Alanine Glycine Glycine Isoleucine Aspartate Glutamate Glutamine Figure 2 | BCAA catabolism is initiated upon adipocyte differentiation. Uptake Secretion (a) Summary of BCAA catabolism and carbon-atom transitions from each BCAA tracer. Abbreviations: Bckdh, branched-chain ketoacid Figure 1 | Characterization of metabolic reprogramming during dehydrogenase; AcCoA, acetyl-CoA; PropCoA, propionyl-CoA. adipocyte differentiation. (a) Contribution of [U-13C ]glucose and 13 13 6 (b) Citrate labeling in 3T3-L1 adipocytes from [U- C6]leucine and [U- C6] 13 [U- C5]glutamine to lipogenic AcCoA for palmitate synthesis in 143B, isoleucine. (c) Mole percent enrichment (MPE) of citrate from each tracer A549, HuH-7 cancer cells and 3T3-L1 pre-adipocytes and adipocytes. substrate in 3T3-L1 pre-adipocytes and adipocytes. (d) MPE of citrate from (b) Uptake and secretion fluxes in 3T3-L1 pre-adipocytes and adipocytes. 13 13 [U- C6]leucine and [U- C6]isoleucine in primary human pre-adipocytes (c) Percentage of intracellular glutamine, serine and glycine pools that were and adipocytes isolated from subcutaneous (SAT) or omental adipose 13 newly synthesized (labeled) from [U- C6]glucose in 3T3-L1 pre-adipocytes tissue (OAT) depots. Data in b–d are from three technical replicates and adipocytes. (d) Net amino acid
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