This work showed that obesity-related inflammation activates cyclin-dependent kinase 5 (Cdk5) in the adipose tissue, which phosphorylates PPARγ at the serine residue at position 273 and results in dysregulation of a subset of PPARγ target genes, with reduced expression of genes with favorable metabolic effects, notably insulin sensitivity. Here, CDK5 is linked to obesity due to melanocortin 4 receptor deficiency.