The CIBERSORT algorithm showed increased M0 and M1, decreased M2 macrophage infiltration in NAFLD with comparison to healthy obese group; (4) After 12 weeks of HFD-feeding, the obesity mice had significantly higher serum TSH and In IHC-stained liver sections of obesity group, the intensity of SPP1 had a significantly increased, while TRβ reduced; (5) In vitro studies have shown SPP1 aggravated lipid deposition in hepatic cells dependent on down-regulating the expression of TRβ and TSH acts to promote secretion of SPP1 in M1 macrophage cells. Here, SPP1 is linked to obesity due to melanocortin 4 receptor deficiency.