In summary, our study identifies a new pathway involving activation of GPR3, β-arrestin2, PKM2, and c-Myc in switching cellular metabolism from oxygen consumption to glycolysis in macrophages, a critical role of KCs in protection from HFD-induced obesity and liver pathogenesis, and the potential of targeting this pathway in DAMs for therapeutic interventions in obesity and NAFLD. This evidence concerns the gene GPR3 and obesity due to melanocortin 4 receptor deficiency.