In summary, we demonstrate that regulation of the expression of ANGPTL4 and PDK4, which are important regulators of glucose and lipid metabolism and insulin resistance, is directly linked to S273 phosphorylation of PPARγ in response to common T2DM factors such as a high-fat diet, obesity, and inflammation. This evidence concerns the gene ANGPTL4 and obesity due to melanocortin 4 receptor deficiency.