Adrenalectomy reduces neuropeptide Y–induced insulin release and NPY receptor expression in the rat ventromedial hypothalamus

Abstract

IntroductionObesity, which is an important risk factor for serious chronic illnesses such as insulin resistance, type 2 diabetes, and heart disease is caused by an imbalance between energy intake and energy expenditure. There are numerous factors influencing whole-body energy balance, including neural and hormonal signals, which, when altered could result in obesity. It is becoming increasingly evident that the central nervous system, particularly the hypothalamus, plays a critical role in integrating these signals to regulate energy balance and that neuropeptide Y (NPY) is an important neuromodulator in this system (1, 2).NPY is widely distributed throughout the brain (3). However, most of the metabolic actions of NPY appear to be mediated through defined hypothalamic nuclei, including the arcuate nucleus (Arc) where numerous NPY-containing neurons originate, the paraventricular nucleus (PVN), where many NPYcontaining arcuate neuron terminals and NPY-binding sites are located, and the ventromedial hypothalamic (VMH) nucleus, which has been referred to as "the satiety center" (3, 4). NPY is the most potent orexigenic agent known (5, 6) and can also cause changes in circulating hormone levels (7). Chronic intracerebroventricular (icv) administration of NPY results in hyperphagia, hyperinsulinemia, insulin resistance, and obesity (8-10). Lesions of the VMH in rodents also cause multiple changes in metabolic status, including hyperphagia, hyperglycemia, and hyperinsulinemia (11). Interestingly, injection of NPY directly into the VMH significantly increases food intake (12), and NPY-induced feeding is enhanced in VMH-lesioned rats (13). These data suggest the VMH may also be a site of action for NPY in the development of obesity; however, the mechanisms by which NPY is involved in each aspect of central energy regulation remain to be defined.Much research has focused on which of the 5 NPYreceptor subtypes cloned so far (Y 1 , Y 2 , Y 4 , Y 5 , and the y6) (14) might mediate the potent NPY-induced feeding response. Several lines of evidence point to the Y 1 -and/or Y 5 -receptor subtypes being the most likely candidates for such an action (15-19). In addition, our previous studies investigating the mRNA expression of all known Y receptors in the rat brain also show clearly that both Y 1 -and Y 5 -receptor subtype mRNAs are expressed in areas pivotal in regulating energy balance (20).Glucocorticoid hormones play a critical role in energy balance and also appear to mediate at least some of their actions through the central NPY axis Chronic central administration of neuropeptide Y (NPY) causes hyperphagia, hyperinsulinemia, and obesity, a response that is prevented by prior adrenalectomy (ADX) in rats. The basis of NPY's effect and how the acute responses to this peptide are affected by ADX remain unknown. This study investigates the role of glucocorticoids in acute NPY-stimulated food intake, acute NPY-induced insulin release, and hypothalamic NPY-receptor mRNA expression levels. NPYinduced food intake was similar in A...

Inhibitory effects of central neuropeptide Y on the somatotropic and gonadotropic axes in male rats are independent of adrenal hormones

“…These increases occurred despite the fact that NPY--infused rats were prevented from overeating by pair--feeding with controls, and that there was no increase in body weight. Adrenalectomy abolished these NPY effects, in keeping with studies showing that other adipogenic effects of NPY are completely prevented or significantly attenuated by prior adrenalectomy in rats [16,23,29,31,34,37,43,45], and restored by specific glucocorticoid replacement [31,34,45]. In adrenalectomized rats, despite significantly reduced basal plasma IGF--1 levels, central NPY infusion was still able to inhibit the somatotropic axis, indicated by further reductions in plasma IGF--1.…”

“…These effects were restored by specific glucocorticoid replacement [31,34,45]. Other studies showed that adrenalectomy or administration of type II adrenal steroid receptor antagonists significantly attenuated or abolished the hyperphagia induced by acute central NPY injection in rats [16,23,34,37], although this was not consistent in all studies [43].…”

Central neuropeptide Y infusion and melanocortin 4 receptor antagonism inhibit thyrotropic function by divergent pathways

“…Acute ICV NPY administration is known to modulate circulating concentrations of corticosterone and insulin (Sainsbury et al, 1996 andWisialowski et al, 2000), both of which -in addition to thyroid hormones -influence energy homoestasis. Moreover, corticosterone and insulin status can have significant effects on thyroid hormone concentrations (Kakucska et al, 1995, Alkemade et al, 2005, Nicoloff et al, 1970, Gonzalez et al, 1980and Mitsuma and Nogimori, 1982.…”

Proopiomelanocortin-Deficient Mice Are Hypersensitive to the Adverse Metabolic Effects of Glucocorticoids

“…Previous studies have examined the effect of lack of glucocorticoids on AgRP and NPY mRNA expression in the hypothalamus (10,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Makimura et al (10) reported that adrenalectomy in wild-type mice reduced AgRP but not NPY mRNA expression.…”