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

Abstract

Weight loss inhibits thyrotropic function and reduces metabolic rate, thereby contributing to weight regain. Under negative energy balance there is an increase in the hypothalamic expression of both neuropeptide Y (NPY) and agouti related peptide (AgRP), the endogenous antagonist of melanocortin 4 (MC4) receptors. Both NPY and MC4 receptor antagonism reduce thyrotropic function centrally, but it is not known whether these pathways operate by similar or distinct mechanisms. We compared the time-course of effects of acute or chronic intracerebroventricular (ICV) administration of NPY (1.2 nmol acute bolus, or 3.5 nmol/day for 6 days) or the MC4 receptor antagonist HS014 (1.5 nmol bolus, or 4.8 nmol/day) on plasma concentrations of thyroid stimulating hormone (TSH) or free thyroxine (T4) in male rats pairfed with vehicle-infused controls. These doses equipotently induced hyperphagia in acute studies, reduced latency to feed, and increased white adipose tissue mass after 6 days of infusion. Acute central NPY but not HS014 administration significantly reduced plasma TSH concentrations within 30-60 min and plasma free T4 levels within 90-120 min. These inhibitory effects were sustained for up to 5-6 days of continuous NPY infusion. HS014 induced a transient decrease in plasma free T4 levels that was observed only after 1-2 days of continuous ICV infusion. While both NPY and HS014 significantly increased corticosteronemia within an hour after ICV injection, the effect of NPY was significantly more pronounced and was sustained for up to 4 days of administration. Both NPY and HS014 significantly decreased the brown adipose tissue protein levels of uncoupling protein-3. We conclude that central NPY and MC4 antagonism decrease thyrotropic function via partially distinct mechanisms with different time courses, possibly involving glucocorticoid effects of NPY. MC4 receptor antagonism increases adiposity via pathways independent of increased food intake or changes in circulating concentrations of TSH, free T4 or corticosterone.

Structural and functional characterization of neuropeptide Y in a primitive teleost, the Japanese eel (Anguilla japonica)

“…On the contrary, NPY exhibits an inhibitory action on the TSHb expression in Japanese eel. Similar findings have been reported in mammals and in bighead carp [15,20,42], suggesting that the role of NPY on the hypothalamic-pituitary-thyroid (HPT) axis is conserved from fish to mammals. It has been proposed that the physiological significance of NPY in suppressing the HPT axis may be associated with maintaining energy homeostasis in organism under conditions of negative energy balance [42].…”

Role of the hypothalamus in the neuroendocrine regulation of body weight and composition during energy deficit

“…Additionally, male and female MC4 receptor knockout mice do not have perturbations in plasma corticosterone concentrations (104). Moreover, whereas chronic central infusion of an MC4 receptor antagonist increases corticosteronemia in male rodents, no such change is seen when animals are pair‐fed with controls to prevent hyperphagia (103,105), demonstrating that the stimulatory effect on corticosteronemia was likely mediated by hyperphagia. Thus, while changes in melanocortin signalling may induce short‐term stimulatory or inhibitory effects on CRH expression or circulating corticosterone levels, they do not appear to exert long‐term regulatory effects on the adrenal axis that would contribute to the changes observed in this axis with energy restriction.…”

“…Corticosteronemia peaked at 30 min and was normalized by 120 min of ICV MTII injection, and the effect was attenuated by blockade of MC4 or CRH receptors (101), demonstrating MC4 receptor-mediated effects on the CRH axis. The physiological significance of this finding is unclear, however, given that acute central administration of the melanocortin receptor antagonists HS014 or AgRP has the same transient stimulatory effect on corticosteronemia (103) or plasma ACTH (102) as the agonists MTII (101) or an a-MSH analogue (102). Additionally, male and female MC4 receptor knockout mice do not have perturbations in plasma corticosterone concentrations (104).…”

Epilepsy and Thyroid Hormones

“…Nöropeptid Y, TSH/T4 konsantrasyonu ile ters ilişkili bir hormondur. [63] Bir çalışmada, nöbetlerin NPY sentezini değiştirdiği saptanmıştır. [64] BOS proteomik çalışmaları, temporal lob epilepsi durumunda vitamin D-bağlayıcı protein düzeyinin arttığını tespit etmiştir.…”