As a crucial metabolic intermediate, l-
lactate is involved in redox balance, energy balance, and acid-base balance in organisms. Moderate exercise training transiently elevates plasma l-
lactate levels and ameliorates
obesity-associated
type 2 diabetes. However, whether moderate l-
lactate administration improves
obesity-associated
insulin resistance remains unclear. In this study, we defined 800 mg/kg/day as the dose of moderate l-
lactate administration. In mice fed with a high-fat diet (HFD), moderate l-
lactate administration for 12 weeks was shown to alleviate
weight gain, fat accumulation, and
insulin resistance. Along with the phenotype alterations, white adipose tissue thermogenesis was also found to be elevated in HFD-fed mice. Meanwhile, moderate l-
lactate administration suppressed the infiltration and proinflammatory M1 polarization of adipose tissue macrophages (ATMs) in HFD-fed mice. Furthermore, l-
lactate treatment suppressed the
lipopolysaccharide-induced M1 polarization of bone marrow-derived macrophages (BMDMs). l-
lactate can bind to the surface receptor GPR132, which typically drives the downstream cAMP-PKA signaling. As a nutrient sensor,
AMP-activated protein kinase (AMPK) critically controls macrophage inflammatory signaling and phenotype. Thus, utilizing inhibitors of the
kinases PKA and AMPK as well as
siRNA against GPR132, we demonstrated that GPR132-PKA-AMPKα1 signaling mediated the suppression caused by l-
lactate treatment on BMDM M1 polarization. Finally, l-
lactate addition remarkably resisted the impairment of
lipopolysaccharide-treated BMDM conditional media on adipocyte
insulin sensitivity. In summary, moderate l-
lactate administration suppresses ATM proinflammatory M1 polarization through activation of the GPR132-PKA-AMPKα1 signaling pathway to improve
insulin resistance in HFD-fed mice, suggesting a new therapeutic and interventional approach to
obesity-associated
type 2 diabetes.