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

Yusuke Adachi, Ana Luisa De Sousa-Coelho, Ikue Harata, Charlie Aoun, Sandra Weimer, Xu Shi, Karina N. Gonzalez Herrera, Hirokazu Takahashi, Chris Doherty, Yasushi Noguchi, Laurie J. Goodyear, Marcia C. Haigis, Robert E. Gerszten, Mary-Elizabeth Patti

Plasma amino acids are dysregulated in obesity. While increased branched chain amino acids may reflect inadequate insulin action, it has also been suggested that amino acids can directly modulate insulin action and may contribute to the pathophysiology of insulin resistance. However, the molecular mechanisms responsible for these effects remain uncertain. Adachi and colleagues report that l-alanine uniquely increases phosphorylation of the nutrient sensor AMP kinase (AMPK) and, in parallel, improves glucose tolerance in vivo in mice.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: Ala may serve as a distinct amino acid energy sensor, providing a positive signal to activate the beneficial AMPK signaling pathway.