The role of lactate in adipose tissue inflammation

Abstract

Obesity is a medical condition characterized by the abnormal accumulation of lipid in the white adipose tissue and is caused by the imbalanced energy uptake and expenditure. It is closely related to a series of metabolic diseases, including cardiovascular diseases, diabetes, and even certain types of cancer. There exists an increased level of inflammation in obese adipose tissue, accompanied by the development of obesity -induced adipose tissue dysfunction. During this process, polarization of macrophage serves as the major effector. With the expansion of the adipocytes in size, hypoxia level in the obese adipose tissue increases, which in turn induces the anaerobic metabolism of glucose and the production of lactate. However, whether and how lactate plays a role in the development of the adipose tissue inflammation and macrophage polarization remains poorly understood. In our study, we demonstrated that the lactate concentration and the protein level of lactate dehydrogenase A (LDHA), the enzyme responsible for producing lactate, in adipose tissue were significantly increased after diet-induced obesity. To further elucidate the physiological role of lactate in pathogenesis of obesity-associated metabolic disorders, adipocyte specific and macrophage specific Ldha knockout (KO) mice were constructed. We found that the adipocyte is the major source of the lactate in adipose tissue. With the high fat diet treatment, the adipocyte specific Ldha KO mice have decreased lactate concentration in the adipose tissue, in accompany with improved systemic glucose metabolism. In addition, the number of adipose tissue macrophages, especially the proinflammatory M1 macrophages, was substantially decreased in the adipocyte-specific Ldha KO mice. Furthermore, we found that the glycolysis and the lactate productions were also significantly increased during the M1 polarization of the macrophages. In addition, the M1 polarization in macrophage was inhibited when the lactate production was inhibited by either pharmacological method or genetic strategy. Replenishment of lactate reversed this effect and upregulated the expression level of the M1 markers, indicating that lactate plays an active role in macrophage polarization. NF-κB and hypoxia inducible factor 1 (HIF-1) pathways, the two major inflammatory pathways, were demonstrated to be augmented by lactate in the M1 polarization process. To further investigate the working mechanism of lactate in macrophage, in vitro activity assays were established. By using these assays, we demonstrated that lactate directly inhibited the activity of prolyl hydroxylase domain-containing protein 2 (PHD2), a hydroxylase that activates the hydroxylation and degradation of both HIF-1α and IκB kinases (IKKs). In summary, these findings support our hypothesis that adipocyte-derived lactate is overproduced in obesity, and thereby inhibits the activity of the PHD2 in macrophages. Inhibition of PHD2 upregulates NF-κB and HIF-1 pathways within macrophages and thus facilitates the M1 polarization. The increased M1 macrophages promote the adipose tissue inflammation and the development of insulin resistance. Therefore, as a small molecule metabolite, lactate serves as the mediator between adipocytes and adipose tissue macrophages, to set the tone for adipose inflammation and systemic metabolism.