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Overexpressing hydroxycarboxylic acid receptor 1 in mouse brown adipose tissue restores glucose tolerance and insulin sensitivity in diet-induced obese mice.

Interscapular BAT (iBAT) plays an important role in the control of glucose homeostasis. Increased glucose entry and glycolysis in iBAT result in lactate production and release. The adipose tissue expresses the lactate receptor hydrocarboxylic acid receptor 1 (HCAR1) that is markedly downregulated in male diet-induced obese (DIO) and ob/ob mice. In this study, we examined the role of HCAR1 in iBAT in controlling glucose homeostasis in male DIO mice. We overexpressed HCAR1 in iBAT by injecting adeno-associated viruses (AAV) expressing HCAR1 into the iBAT pads of male DIO C57BL/6J mice. Overexpressing HCAR1 in iBAT resulted in augmented glucose uptake by iBAT in response to treatment with the HCAR1 agonist. HCAR1 overexpression elevated iBAT temperature associated with increased thermogenic gene expression in iBAT. HCAR1 overexpression prevented body weight gain in male DIO mice. Importantly, mice overexpressing HCAR1 in iBAT exhibited improved glucose tolerance and insulin sensitivity. HCAR1 overexpression upregulated the Slc2a4 gene expression and promoted GLUT4 trafficking to the plasma membrane. In addition, mice overexpressing HCAR1 displayed a decrease in HSL phosphorylation and increased lipogenic enzyme gene expression in iBAT. Unlike DIO mice, overexpressing HCAR1 in iBAT of mice fed a low-fat diet did not change body weight gain and glucose homeostasis. Taken together, our results support the interpretation that HCAR1 expressed in iBAT promotes glucose entry and reduces lipolysis in iBAT of male DIO mice. As activation of HCAR1 in iBAT restores body weight, glucose tolerance, and insulin sensitivity in male DIO mice, targeting HCAR1 in iBAT would provide an alternative way to control body weight and euglycemia in individuals with obesity.