In conclusion, our study indicates that TPH2, the predominant TPH isoform in the CNS, is dramatically upregulated in adipocytes by obesity-induced hyperinsulinemia altering systemic metabolism, and adipocyte-specific inhibition of TPH2 could be a promising therapeutic intervention for DIO and its metabolic complications. This evidence concerns the gene TPH2 and obesity due to melanocortin 4 receptor deficiency.