In preclinical studies, Nrg4 as a novel endocrine checkpoint exerted protective effects against various metabolic diseases such as IR, obesity, NAFLD, and diabetes; while discrepancies were noted in clinical investigations, more well-designed studies with large samples are needed in the future to address the heterogeneity and inconsistency. The gene discussed is NRG4; the disease is obesity due to melanocortin 4 receptor deficiency.