INS and obesity due to melanocortin 4 receptor deficiency: • Accelerated aging (reduced mitochondrial function and increased susceptibility to oxidative stress) • Developed global glucose intolerance and insulin resistance • Upon HFD: • Obesity, insulin-insensitive, and refractory to the glucose lowering effects of TZD and AICAR, energy metabolism shifts from OxPhos to glycolysis • Mesenteric adipose tissue: adipocyte hypertrophy and increased inflammatory • Liver: hepatosteatosis • BAT: reduced thermogenic capacity and mitochondrial biogenesis