Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis

• Published in: Nature chemical biology Vol. 12; no. 1; pp. 15 - 21
• Main Authors: Green, Courtney R, Wallace, Martina, Divakaruni, Ajit S, Phillips, Susan A, Murphy, Anne N, Ciaraldi, Theodore P, Metallo, Christian M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-01-2016; Nature Publishing Group
• Subjects: 13/109; 13/89; 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) - genetics; 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) - metabolism; 38/77; 3T3-L1 Cells - drug effects; 631/443/319; 631/45; 631/92/1643; 631/92/320; 82/58; Acetyl Coenzyme A - metabolism; Adipocytes; Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - metabolism; Adipogenesis - physiology; Adipose tissue; Adipose Tissue - cytology; Adipose Tissue - metabolism; Amino acids; Amino Acids, Branched-Chain - metabolism; Animals; Base Sequence; Biochemical Engineering; Biochemistry; Biology; Bioorganic Chemistry; Body fat; Cell Biology; Cell Differentiation - drug effects; Cell Differentiation - physiology; Chemistry; Chemistry/Food Science; Fatty acids; Glucose; Homeostasis; Humans; Insulin; Lipids; Lipogenesis; Metabolism; Metabolites; Mice; Molecular Sequence Data; Obesity - metabolism; Obesity - surgery; Oxidation; Tricarboxylic Acids - metabolism; Vitamin B 12 - pharmacology; La Jolla California; United States > US; California
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.1961

Stable-isotope tracing and metabolomics analysis comparing pre-adipocytes and differentiated adipocytes revealed a shift from glucose and glutamine utilization to increased branched chain amino acid catabolic flux to generate acetyl–coenzyme A.
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.