IRS2 and obesity due to melanocortin 4 receptor deficiency: Promote inflammation (Liu et al., 2008; Liu et al., 2015). Negative regulator of leptin receptor signaling, can inhibit fatty acid oxidation and mediate leptin resistance and diet-induced obesity (Bjorbak et al., 2000; Steinberg et al., 2006). Can impair insulin sensitivity via degradation of IRS1 and IRS2 or inhibition of receptor tyrosine phosphorylation (Rui et al., 2002; Senn et al., 2003). Socs3 tissue specific deficiency enhanced insulin sensitivity and protected against obesity- associated insulin resistance (Sachithanandan et al., 2010; Jorgensen et al., 2013).