Second, our results in HFD-fed mice provide evidence that circadian dysfunction actually precedes the development of metabolic inflammation (upregulation of Ccl2, Loxl2, Pai1 and downregulation of Mmp2), thereby suggesting that changes in BMAL1 binding as well as other changes in chromatin state might occur very early during the development of obesity. Here, BMAL1 is linked to obesity due to melanocortin 4 receptor deficiency.