l-Alanine activates hepatic AMP-activated protein kinase and modulates systemic glucose metabolism

AMP activated protein kinase (AMPK) is recognized as an important nutrient sensor contributing to regulation of cellular, tissue, and systemic metabolism. We aimed to identify specific amino acids which could modulate AMPK and determine effects on cellular and systemic metabolism. We performed an unbiased amino acid screen to identify activators of AMPK. Detailed analysis of cellular signaling and metabolism was performed in cultured hepatoma cells, and in vivo glucose metabolism and metabolomic patterns were assessed in both chow-fed mice and mice made obese by high-fat diet feeding. Alanine acutely activates AMP kinase in both cultured hepatic cells and in liver from mice treated in vivo with Ala. Oral alanine administration improves systemic glucose tolerance in both chow and high fat diet fed mice, with reduced efficacy of Ala in mice with reduced AMPK activity. Our data indicate that Ala activation of AMPK is mediated by intracellular Ala metabolism, which reduces TCA cycle metabolites, increases AMP/ATP ratio, and activates NH3 generation. Ala may serve as a distinct amino acid energy sensor, providing a positive signal to activate the beneficial AMPK signaling pathway. [Display omitted] •Unbiased amino acid screen identified alanine as a unique activator of AMP kinase.•Alanine acutely activates AMP kinase in both cultured cells and in vivo.•Alanine and NH3 metabolism contribute to regulation of AMP kinase activation.•Effects of Ala are reduced in absence of AMP kinase.•Oral alanine improves glucose tolerance in vivo in both chow and HFD-fed mice.