Exercise ameliorates adipose tissue insulin resistance by activating the lactate/GPR81 signaling pathway in DIO-IR mice

Growing evidence indicates that both exogenous lactate administration and physical exercise improve insulin resistance (IR). This study investigates, from a novel perspective, whether exercise-induced lactate serves as a signaling molecule to ameliorate adipose tissue IR and explores the underlying mechanisms. Using diet-induced obese and insulin-resistant (DIO-IR) mice subjected to high-lactate exercise training, insulin-resistant 3T3-L1 (IR-3T3-L1) adipocytes treated with lactate, and a GPR81-overexpressing cell line, we demonstrate three key findings: First, high-lactate exercise training markedly alleviated adipose tissue and systemic IR in DIO-IR mice. Second, acute high-lactate exercise mirrored the effects of L-lactate injection by elevating circulating and epididymal white adipose tissue (eWAT) lactate concentrations, concomitantly upregulating GPR81 and glucose uptake signaling expression while modulating adipokine secretion. Mechanistically, lactate/GPR81 signaling potentiated glucose uptake in IR-3T3-L1 adipocytes via the IRS1-AKT-GLUT4 pathway. Collectively, these results demonstrate that exercise-induced lactate enhances glucose uptake signaling and rebalances adipokine secretion. It may act as a signaling molecule that upregulates the specific receptor GPR81, thereby alleviating adipose tissue and systemic insulin resistance in diet-induced obese insulin-resistant (DIO-IR) mice. Our findings uncover a previously unrecognized link between exercise metabolism and adipose tissue homeostasis, highlighting lactate as a potential therapeutic target for IR-related metabolic disorders.