SIRT4 is an early regulator of branched-chain amino acid catabolism that promotes adipogenesis

Upon nutrient stimulation, pre-adipocytes undergo differentiation to transform into mature adipocytes capable of storing nutrients as fat. We profiled cellular metabolite consumption to identify early metabolic drivers of adipocyte differentiation. We find that adipocyte differentiation raises the uptake and consumption of numerous amino acids. In particular, branched-chain amino acid (BCAA) catabolism precedes and promotes peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of adipogenesis. In early adipogenesis, the mitochondrial sirtuin SIRT4 elevates BCAA catabolism through the activation of methylcrotonyl-coenzyme A (CoA) carboxylase (MCCC). MCCC supports leucine oxidation by catalyzing the carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA. Sirtuin 4 (SIRT4) expression is decreased in adipose tissue of numerous diabetic mouse models, and its expression is most correlated with BCAA enzymes, suggesting a potential role for SIRT4 in adipose pathology through the alteration of BCAA metabolism. In summary, this work provides a temporal analysis of adipocyte differentiation and uncovers early metabolic events that stimulate transcriptional reprogramming. [Display omitted] •Branched-chain amino acid (BCAA) oxidation drives early adipocyte differentiation•BCAA catabolism precedes PPARγ transcriptional activity•The mitochondrial sirtuin SIRT4 promotes BCAA catabolism and adipogenesis•The SIRT4-BCAA catabolism axis is downregulated in the adipose tissue of diabetic mice Although adipose tissue expands and shrinks in response to nutrients, the involvement of mitochondrial signaling in adipose tissue biology has remained elusive. Zaganjor et al. identify an early regulator of adipogenesis, a mitochondrial sirtuin, SIRT4, which promotes the process through the induction of branched-chain amino acid catabolism.