Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice

To elucidate the role of neuropeptide Y (NPY)-Y1 receptor (Y1-R) in food in take, energy expenditure, and other possible functions, we have generated Y 1-R-deficient mice (Y1-R-/-) by gene targeting. Contrary to our hypothesis that the lack of NPY signaling via Y1-R would result in impaired feeding an d weight loss, Y1-R-/- mice showed a moderate obesity and mild hyperinsulin emia without hyperphagia. Although there was some variation between males a nd females, typical characteristics of Y1-R-/- mice include: greater body w eight (females more than males), an increase in the weight of white adipose tissue (WAT) (approximately 4-fold in females), an elevated basal level of plasma insulin (approximately 2-fold), impaired insulin secretion in respo nse to glucose administration, and a significant changes in mitochondrial u ncoupling protein (UCP) gene expression (up-regulation of UCP1 in brown adi pose tissue and down-regulation of UCP2 in WAT). These results suggest eith er that the Y1-R in the hypothalamus is not a key molecule in the leptin/NP Y pathway, which controls feeding behavior, or that its deficiency is compe nsated by other receptors, such as NPY-Y5 receptor. We believe that the mil d obesity found in Y1-R-/- mice (especially females) was caused by the impa ired control of insulin secretion and/or low energy expenditure, including the lowered expression of UCP2 in WAT. This model will be useful for studyi ng the mechanism of mild obesity and abnormal insulin metabolism in noninsu lin-dependent diabetes mellitus.