INS and obesity due to melanocortin 4 receptor deficiency: For example, the absence of negative regulators of PI3K/Akt, such as PTP1B and PTEN (antagonists of insulin signaling), improves insulin sensitivity and protects against diet-induced IR in mice [35,36]; in contrast, systemic reduction in PI3K signaling by PTEN overexpression [37], or targeted inhibition of PI3K isoforms, increases energy expenditure and protects from obesity and metabolic syndrome [38,39].