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

Abstract

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 leptin͞NPY 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 and͞or 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.

To subjugate NPY is to improve the quality of life and live longer

“…Results from diverse molecular and genetic paradigms are consistent with the implication that NPY, in concert with co-expressed orexigenic AgrP, GABA and adrenergic transmitters, constitutes an obligatory orexigenic signaling modality that is intimately involved in propagation of the timely appetitive drive under the direction of photoperiodic and hormonal cues (7,11,(27)(28)(29)47,(49)(50)(51)54,(56)(57)(58)(59). Additional recent disclosures that the hard wiring for the timely operation of this interplay is established during postnatal development have put the notion that NPY is a physiological appetite transducer on firm footing (11,(28)(29)(30)49,64).…”

“…In addition to a pivotal role in hypothalamic integration of energy homeostasis, the hypothalamic NPY network has since been shown to play a role in neuroendocrine control of reproduction and lactation, fluid balance, growth, stress, temperature, general body metabolism and bone health (1,12,15,31,41,45,46,48,62). It is now obvious that disruption in any one or more loci in the hypothalamic network of NPY and cohorts inflicted by environmental or genetic factors leads to several metabolic and neuroendocrine diseases that adversely affect the quality of life and life span (1,4,(24)(25)(26)30,32,47). The focus of this review is to summarize our recent efforts to characterize the potential health benefit of experimentally imposed lifetime restraint on hypothalamic NPYergic signaling by leptin, the endogenous adipocyte hormone that is intimately involved in the hypothalamic integration of energy and neuroendocrine homeostasis (2,3,9,10,(12)(13)(14)(15)(19)(20)(21)23,33,37,38,42,48,60,61).…”

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

“…In keeping with this, body weight was not affected when haloperidol was administered orally to male rats for three or six weeks (Minet-Ringuet et al, 2005 andPouzet et al, 2003), and was even suppressed under the longer treatment period of 80 weeks (Yoshida et al, 1995). The early stages of obesity, indicated by an increase in percent body fat, have been observed even in the absence of increases in body weight or food intake (Kushi et al, 1998, Pedrazzini et al, 1998and Sainsbury et al, 1997. This is due to preferential channelling of fuels from lean tissues such as muscle and bone towards white This study examined the effects of chronic subcutaneous infusion of supratherapeutic doses of a typical (haloperidol) and an atypical (risperidone) antipsychotic drugs on endocrine functions and metabolic profile in male SpragueeDawley axes (testosterone), the two antipsycho on endocrine activities, with haloperido insulin levels and risperidone incre levels.…”

Receptor subtypes Y1 and Y5 mediate neuropeptide Y induced feeding in the guinea‐pig

“…Mice lacking the NPY gene were initially reported to show no changes in feeding and metabolism unless crossed with mice having a genetic defect in the leptin gene, but later studies did observe reduced food intake and body weight (Erickson et al, 1996). When each of the NPY receptor genes was disrupted, there was a late-onset increase in body weight, both for Y 1 and Y 5 as well as for Y 2 (Kanatani et al, 2000b;Kushi et al, 1998;Marsh et al, 1998;Naveilhan et al, 1999;Pedrazzini et al, 1998).…”