Impact of obesity on aromatic amino acids and brain glucose during acute hyperglycemia

Hyperaminoacidemia is an early hallmark of insulin resistance, with aromatic and branched chain amino acids particularly associated with insulin resistance and type 2 diabetes. We previously showed that healthy adults with obesity exposed to acute hyperglycemia have lower brain glucose levels measured by magnetic resonance spectroscopy than lean controls, suggesting that a blunted brain response to hyperglycemia may be an early marker of insulin resistance. Here, in a secondary analysis of our prior study, we used targeted mass spectrometry-based metabolomics to measure plasma amino acids in participants with and without obesity to determine whether changes in peripheral metabolites associated with early insulin resistance such as amino acids were associated with changes in brain glucose levels during hyperglycemia. There were few differences in baseline amino acids between groups, but acute hyperglycemia unveiled higher plasma concentrations of amino acids including cysteine, cystine, glutamic acid, glutamine, methionine, and aromatic amino acids in obesity. Plasma glucagon levels were also higher in obesity during acute hyperglycemia. Higher plasma concentrations of aromatic amino acids and glucagon were significantly correlated with lower brain glucose levels, illustrating parallel development of central and peripheral metabolic changes in obesity.<b>NEW & NOTEWORTHY</b> We related early insulin resistance-associated peripheral factors with brain glucose measured by ¹³C magnetic resonance spectroscopy during acute hyperglycemia in young, healthy adults with and without obesity. Plasma amino acids including aromatic amino acids and glucagon were higher in obesity during acute hyperglycemia. There were negative correlations between aromatic amino acids and glucagon with the change in brain glucose. These findings may be related to brain oxidative stress and neurotransmitter synthesis in obesity.