Adipocyte-Derived Lactate Potentiates Obesity-Evoked Adipose Macrophage Inflammation

Abstract Introduction: Obesity is characterized by mobilization of macrophage inflammation, which represents the major events of obesity-associated adipose tissue inflammation. . On the other hand, lactate accumulation in adipose tissue long been observed. However, whether elevation of lactate plays an essential role in adipose inflammation is not known. In this study, we sought to examine the intermediary role of lactate in macrophage polarization and adipose inflammation upon obesity. Method: Lactate level and activity of lactate dehydrogense (LDH), the key enzyme of lactate production, were measured by biochemical assays. Adipocyte- and macrophage- specific Ldha knock out mice were constructed by cre-LoxP system to study the physiological role of lactate in diet induced obesity. Macrophage polarization and inflammation were examined by western blotting and Q-PCR. Results: Lactate and LDH activity were selectively upregulated in adipose tissues of obese mice. Adipocyte-, but not macrophage-selective deletion of LDHA, led to a significant improvement of adipose inflammation and metabolic dysfunctions. In vitro experiments showed that the lactate promoted M1 polarization through direct interation and inhibition of the PHD2, which subsequently stabilizes HIF-1alpha. In addition, a positive correlation between adipose lactate level and adipose tissue inflammation was found in obese patients. Conclusion: In obese condition, increased production of lactate from adipocytes enhances adipose tissue inflammation by promoting the proinflammatory polarization of adipose macrophages.