Author(s): MIYAZAKI, T., UEDA H, IKEGAMI T, HONDA A, Institution: TOKYO MEDICAL UNIVERSITY, Country: JAPAN, Abstract-ID: 944

INTRODUCTION:
During prolonged endurance exercise, branched-chain amino acids (BCAAs)—valine, leucine, and isoleucine—are catabolized in skeletal muscle as alternative energy substrates to compensate for reduced glucose supply. 3-hydroxyisobutyric acid (3HIB), a mitochondrial intermediate of valine catabolism, is released from muscle into the systemic circulation. We previously demonstrated that intraperitoneal administration of 3HIB rapidly and transiently elevates blood glucose levels in rats. In this study, we investigated the mechanisms by which 3HIB influences blood glucose levels, focusing on sympathetic nerve activity and hepatic gluconeogenesis.
METHODS:
Ten-week-old male ICR mice were intraperitoneally injected with 3HIB (60 mg/kg body weight) alone or in combination with the α-adrenergic blocker prazosin (5 mg/kg body weight). Hepatocyte cell lines (HepG2 and AML12) were incubated with gluconeogenic precursors (10 mM 3HIB, 1 mM lactate, 10 mM alanine, and 10 mM glutamate) and/or noradrenaline (NE) for 18 h. Ligand activities of 3HIB toward G-protein–coupled free fatty acid receptors (GPR41 and GPR43) and the γ-aminobutyric acid type B receptor (GABABR) were assessed using GPCR ligand-binding assays.
RESULTS:
In mice injected with 3HIB, blood glucose and NE levels were significantly increased 15 min after injection compared with baseline and returned to basal levels by 60 min. These effects were abolished by prazosin administration. Correspondingly, hepatic concentrations of glucose, fumarate, and malate, as well as mRNA expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, were significantly elevated at 15 min. In cultured hepatocytes, glucose production was robustly stimulated by lactate, whereas 3HIB and other amino acid precursors induced only weak glucose production, even in the presence of NE. 3HIB exhibited agonistic activity toward GPR41 at concentrations as low as approximately 70 μM and toward GPR43 at approximately 600 μM, but showed no activity toward GABA𝐵R.
CONCLUSION:
These findings suggest that the blood glucose–elevating effect of 3HIB is mediated by activation of hepatic gluconeogenesis through stimulation of the sympathetic nervous system, likely via its agonistic action on GPR41. In contrast, 3HIB itself does not appear to be an efficient substrate for gluconeogenesis. During extreme endurance exercise, 3HIB may function as a myokine-like signaling molecule that rapidly enhances hepatic glucose output to meet the metabolic demands of skeletal muscle.