BCAAs acutely drive glucose dysregulation and insulin resistance: role of AgRP neurons

BACKGROUND: High-protein diets are often enriched with branched-chain amino acids (BCAAs) known to enhance protein synthesis and provide numerous physiological benefits, but recent studies reveal their association with obesity and diabetes. Protein or BCAA supplementation has been shown to disrupt glucose metabolism while restriction improves it. It is unclear if these are primary, direct effects of BCAAs or secondary to other physiological changes during chronic manipulation of dietary BCAAs. METHODS: Three-month-old C57Bl/6 mice were acutely treated with vehicle/BCAAs or BT2, a BCAA-lowering compound, and underwent detailed in vivo metabolic phenotyping including frequent sampling and pancreatic (hyperinsulinemic-euglycemic) clamps. RESULTS: A single infusion of BCAAs acutely elevated blood glucose and plasma insulin in male mice. Pre-treatment with BCAAs did not affect glucose tolerance, but a constant infusion of BCAAs during clamps impaired whole-body insulin sensitivity. A single injection of BT2 prevented the fasting-induced rise of plasma BCAAs and markedly improved glucose tolerance in high-fat-fed mice, suggesting that abnormal glycemic control in obesity may be causally linked to high circulating BCAAs. Chemogenetic over-activation of hypothalamic AgRP neurons impaired glucose tolerance that was completely normalized by acute BCAA reduction. Most effects were observed in male, not female, mice. CONCLUSION: BCAAs per se can acutely impair glucose homeostasis and insulin sensitivity, offering a mechanism for long-term disruption of glucose metabolism in obesity and diabetes. AgRP neuronal regulation of blood glucose is mediated through BCAAs, revealing a brain-to-metabolism mechanism controlling glucose homeostasis.