Dietary Lactate Intake and Physical Exercise Synergistically Reverse Brown Adipose Tissue Whitening to Ameliorate Diet-Induced Obesity

Physical exercise represents an effective strategy for combating obesity via brown adipose tissue (BAT) activation, but the mechanism remains unclear. In this study, we demonstrated that the cooperation between lactate and adrenoceptor signaling regulated BAT activity during exercise. The lactate receptor GPR81 was highly expressed in the BAT of lean mice, whereas its expression was markedly decreased in obese mice. Notably, the level of GPR81 in BAT could be upregulated by exercise. The blockade of lactate production or GPR81 significantly impaired exercise-induced BAT activation. In addition, dietary lactate intake enhanced the efficacy of physical exercise in alleviating BAT whitening in obese mice, as evidenced by the improved mitochondrial ultrastructure, reduced lipid droplets, increased UCP1 expression, and elevated mitochondrial DNA content. Further data indicated that norepinephrine triggered UCP1 activation through both the cAMP/PKA and Ca²⁺/CaMK pathways during exercise, while lactate mediated this process via the GPR81-Ca²⁺/CaMK cascade. Our findings unveil a novel mechanism in the regulation of BAT function by physical exercise, providing a promising lifestyle intervention to improve metabolic health.