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. The gene discussed is GPR3; the disease is metabolic dysfunction-associated steatotic liver disease.