In this study, we used in vivo and in vitro models to demonstrate that adipocyte Serpina3c inhibited Nrf2 expression to reduce Hif1α transcription, thereby reducing glycolysis and DNL, ultimately ameliorating obesity, hypertriglyceridemia, and metaflammation induced by HFD. This evidence concerns the gene NFE2L2 and obesity due to melanocortin 4 receptor deficiency.