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 intake, energy expenditure, and other possible functions, we have generated Y1-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 and weight loss, Y1-R-/- mice showed a moderate obesity and mild hyperinsulinemia without hyperphagia. Although there was some variation between males and females, typical characteristics of Y1-R-/- mice include: greater body weight (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 response to glucose administration, and a significant changes in mitochondrial uncoupling protein (UCP) gene expression (up-regulation of UCP1 in brown adipose tissue and down-regulation of UCP2 in WAT). These results suggest either that the Y1-R in the hypothalamus is not a key molecule in the leptin/NPY pathway, which controls feeding behavior, or that its deficiency is compensated by other receptors, such as NPY-Y5 receptor. We believe that the mild obesity found in Y1-R-/- mice (especially females) was caused by the impaired control of insulin secretion and/or low energy expenditure, including the lowered expression of UCP2 in WAT. This model will be useful for studying the mechanism of mild obesity and abnormal insulin metabolism in noninsulin-dependent diabetes mellitus.
Kushi
A
A
Central Pharmaceutical Research Institute, Pharmaceutical Frontiers Research Laboratory, Japan Tobacco Inc., 1-13-2, Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236, Japan.
Sasai
H
H
Koizumi
H
H
Takeda
N
N
Yokoyama
M
M
Nakamura
M
M
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001831:Body Temperature; D001835:Body Weight; D016887:Cardiopulmonary Resuscitation; D002678:Chimera; D005247:Feeding Behavior; D005260:Female; D015698:Genomic Library; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology; D017476:Receptors, Neuropeptide Y / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012727:Sex Characteristics
D001786:Blood Glucose; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor