A cell-autonomous mechanism regulates BCAA catabolism in white adipocytes and systemic metabolic balance

Abstract Elevated plasma branched-chain amino acids (BCAAs) are strongly associated with obesity, insulin resistance (IR), and diabetes in humans and rodent models. However, the mechanisms of BCAA dysregulation and its systemic, organ, and cell-specific implications in the development of obesity and IR are not well understood. To gain mechanistic insight into the causes and effects of plasma BCAA elevations, we leveraged mouse models with high circulating BCAA levels prior to the onset of obesity and IR. Young mice lacking ankyrin-B in white adipose tissue (WAT) or bearing an ankyrin-B variant that causes age-driven metabolic syndrome exhibit downregulation of BCAA catabolism selectively in WAT and excess plasma BCAAs. Using cellular assays, we demonstrated that ankyrin-B promotes the surface localization of the amino acid transporter Asct2 in white adipocytes, and its deficit impairs BCAA uptake. Excess BCAA supplementation worsened glucose tolerance and insulin sensitivity across genotypes. In contrast, BCAA overconsumption only increased adiposity in control mice, implicating WAT utilization of BCAAs in their obesogenic effects. These results shed light into the mechanistic underpinnings of metabolic syndrome caused by ankyrin-B deficits and provide new evidence of the relevance of WAT in the regulation of systemic BCAA levels, adiposity, and glucose homeostasis. ARTICLE HIGHLIGHTS Ankyrin-B deficits in adipose tissue result in elevated circulating BCAAs before the onset of obesity and insulin resistance. Ankyrin-B promotes the surface localization of the amino acid transporter Asct2 in white adipocytes and BCAA uptake. Excess BCAA supplementation worsens glucose tolerance and insulin sensitivity in ankyrin-B deficient mice. BCAA utilization by white adipose tissue is required for the obesogenic effects of BCAA overconsumption.