Chronic Central Melanocortin-4 Receptor Antagonism and Central Neuropeptide-Y Infusion in Rats Produce Increased Adiposity by Divergent Pathways

Abstract

Increased hypothalamic neuropeptide-Y (NPY) action and disruption of the melanocortin (MC)-4 receptor both result in hyperphagia and obesity. To determine whether similar hormonal and metabolic mechanisms are involved in these two obesity syndromes, we investigated the time course of effects induced by 6-day intracerebroventricular (ICV) infusion of NPY (3.5 nmol/day) or the MC4 receptor antagonist HS014 (4.8 nmol/day) in rats pair-fed with vehicle-infused controls. The weight of white adipose tissue (WAT) deposits was increased after 6-day NPY and HS014 infusion compared with controls, and the increase was significantly greater in HS014-than in NPY-infused rats (retroperitoneal WAT: NPY 0.57 ؎ 0.05; HS014 0.80 ؎ 0.05; control 0.43 ؎ 0.03% body wt, n ‫؍‬ 8 -13, P < 0.05). Plasma leptin was also increased in both experimental groups (NPY 10.6 ؎ 1.9; HS014 4.4 ؎ 0.9; control 2.0 ؎ 0.1 ng/ml, n ‫؍‬ 8 -13, P < 0.05 for all comparisons). Basal plasma corticosterone and insulin levels were increased by ICV NPY infusion, whereas HS014-infused rats showed no significant increase in these parameters on any of 1-6 days of infusion. Both NPY and HS014 infusion potentiated intravenous glucose-induced (300 mg/kg) plasma insulin levels, and there was no difference in glycemia among groups. In NPY-infused rats, the plasma free fatty acid levels were decreased and triglyceridemia was increased compared with controls, but these parameters were unchanged in HS014-infused rats. Hepatic triglyceride content was significantly increased by HS014 but not by NPY infusion. Levels of uncoupling protein-1 mRNA in brown adipose tissue were significantly decreased after 6 days of HS014 infusion, similar to the effect of central NPY. Because ICV HS014 induced at least as great an increase in fat mass as ICV NPY and yet had divergent hormonal and metabolic effects, we conclude that MC4 receptor antagonism does not induce obesity solely by regulation of the endogenous NPY-ergic system. Diabetes 51:152-158, 2002 N europeptide-Y (NPY) is a highly potent orexigenic peptide synthesized in the brain (1). Genetically obese ob/ob and db/db mice and fa/fa rats exhibit a lack of leptin function as their primary defect (2-5), and all exhibit increased NPY expression and secretion in the hypothalamus (6) caused by a lack of leptin's known inhibitory effect on NPY-ergic activity (7). Although other peptides are likely to be involved (1), this increase in hypothalamic NPY probably contributes to obesity in ob/ob, db/db, and fa/fa rodents because intracerebroventricular (ICV) infusions of NPY in normal rodents produce effects similar to those seen in the genetically obese rodent models. These include increased food intake, body weight, fat accumulation, plasma insulin, leptin, and corticosterone concentrations, decreased brown adipose tissue (BAT) thermogenesis, and inhibition of the somatotropic and gonadotropic axes (8 -12).Several dominant mutations at the agouti locus in the mouse also cause a syndrome of marked obesity, hyperinsulinemia, insulin resist...

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

“…This is consistent with data showing that whereas chronic ICV NPY or MC4 receptor antagonist infusion significantly increased body weight in ad libitum-fed rats, no such increase is observed when hyperphagia is prevented by pair-feeding with vehicle-infused controls ( Baran et al, 2002).…”

“…Rats that were made insulin deficient by the administration of streptozotocin showed decreases in circulating levels of TSH, T3 and T4 as well as pituitary TSH and hypothalamic TRH content (Gonzalez et al, 1980 andMitsuma andNogimori, 1982). Thus, it is unlikely that the hyperinsulinemia observed after acute (this study) and chronic (Baran et al, 2002) ICV NPY but not HS014 administration in pair fed rats could contribute to the differences in effects on thyroid hormone concentrations presently observed, in keeping with the observation that insulin administration is unable to prevent the fasting-induced reduction in thyrotropic axis in rats . Taken together, these findings show that acute and chronic ICV NPY administration results in significantly more pronounced and more prolonged hypercorticosteronemia than MC4 receptor antagonism with HS014, and this difference could contribute to the marked and prolonged inhibition in circulating TSH and free T4 levels that are seen in NPY-relative to HS014-infused rats.…”

“…5, brown adipose tissue UCP-3 protein levels were significantly decreased in both NPY-and HS014-infused rats relative to vehicle-infused controls after 6 days of ICV administration. Previous work from our group and others has shown that 3-7 days central NPY, HS014 or AgRP infusion in rats also results in significant decreases in the mRNA expression of brown adipose tissue UCP-1 (Baran et al, 2002, Fekete et al, 2002aand Fekete et al, 2002b, another protein that is regulated by thyroid function. Taken together, these data do not suggest that NPY and HS014 have differential effects on overall thyroid function within brown adipose tissue.…”

“…There was no significant difference among the three groups of rats with respect to body weight at the time of injection (data not shown). We have shown previously that the acute doses of NPY (1.2 nmol) and HS014 (1.5 nmol) chosen for this study were equipotent in that both agents produced an equivalent, 10-fold increase in total food intake in the 4 h after ICV injection compared to vehicle-injected controls (Baran et al, 2002). Despite comparable actions on food intake in rats that were allowed to eat, only NPY injection had effects on thyroid function.…”

Interactions between the melanocortin system and the hypothalamo–pituitary–thyroid axis

“…A single ICV injection of α-MSH increases BAT temperature and BAT sympathetic nerve activity, whereas conversely, these are decreased by AgRP [67]. Similarly, prolonged ICV administration of the synthetic MC4-R antagonist HS014 suppresses BAT UCP-1 mRNA levels [2], yet chronic peripheral injection of the MC4-R agonist MTII is associated with an increase [10].…”