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

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 G protein-coupled receptor 81 (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 insulin receptor substrate 1 (IRS1)-AKT-glucose transporter 4 (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 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.NEW & NOTEWORTHY Exercise-induced lactate as a critical signaling molecule that ameliorates insulin resistance in obesity. Lactate enhances adipose tissue glucose uptake and rebalances adipokine secretion by upregulating the receptor G protein-coupled receptor 81 (GPR81). The findings establish lactate as an essential exercise metabolite with therapeutic potential for metabolic disorders.