The exact mechanisms responsible for the obesity-related BCAA dysregulation remain poorly understood, but may be attributed to the following two reasons: 1) the impaired central nerves system insulin signaling under obesity (28); 2) HFD-induced hyperglycemia which inhibits CREB-stimulated KLF15 transcription resulting in downregulation of enzymes in the BCAA catabolism pathway (29). The gene discussed is ARID4B; the disease is obesity due to melanocortin 4 receptor deficiency.