Obesity in insulin receptor substrate-2-deficient mice: Disrupted control of arcuate nucleus neuropeptides

Objective: Disturbances in insulin signaling have been shown to induce obesity and/or hyperphagia in brain insulin receptor or insulin receptor substrate-2 (IRS-2) knockout (KO) mice. This study aimed to examine the central and peripheral mechanisms underlying the phenotype in IRS-2 KO mice. Research Methods and Procedures: We measured the histological characterization of adipose tissues, mRNA levels of pro-opiomelanocortin, agouti-related protein, and neuropeptide Y in the hypothalamus and uncoupling proteins (UCPs) in peripheral tissues of IRS-2 KO mice. Results: Female IRS-2 KO mice showed increased daily food intake. Body weight and adiposity were increased in both sexes, although these differences were more pronounced in female than in male IRS-2 KO mice. Both male and female IRS-2 KO mice showed decreased UCP1 mRNA expression in brown adipose tissue with defective thermoregulation, and UCP2 mRNA expression was increased in the white adipose tissue of female knockout mice. Furthermore, arcuate nucleus mRNA expression of proopiomelanocortin, was decreased in both male and female IRS-2 KO mice, whereas expression of agouti-related protein and neuropeptide Y were increased in female IRS-2 KO mice. Discussion: In IRS-2 KO mice, disrupted control of hypothalamic neuropeptide levels and UCP mRNA expression may contribute to the development of obesity.