Attenuated hypothalamic responses to α‐melanocyte stimulating hormone during pregnancy in the rat

Abstract

Key pointsr Increased appetite and weight gain occurs during pregnancy, associated with development of leptin resistance, and satiety responses to the anorectic peptide α-melanocyte stimulating hormone (α-MSH) are suppressed.r This study investigated hypothalamic responses to α-MSH during pregnancy, using c-fos expression in specific hypothalamic nuclei as a marker of neuronal signalling, and in vivo electrophysiology in supraoptic nucleus (SON) oxytocin neurons, as a representative α-MSH-responsive neuronal population that shows a well-characterised α-MSH-induced inhibition of firing.r While ICV injection of α-MSH significantly increased the number of c-fos-positive cells in the paraventricular, supraoptic, arcuate and ventromedial hypothalamic nuclei in non-pregnant rats, this response was suppressed in pregnant rats. Similarly, SON oxytocin neurons in pregnant rats did not demonstrate characteristic α-MSH-induced inhibition of firing that was observed in non-pregnant animals.r Given the known functions of α-MSH in the hypothalamus, the attenuated responses are likely to facilitate adaptive changes in appetite regulation and oxytocin secretion during pregnancy.Abstract During pregnancy, a state of positive energy balance develops to support the growing fetus and to deposit fat in preparation for the subsequent metabolic demands of lactation. As part of this maternal adaptation, the satiety response to the anorectic peptide α-melanocyte stimulating hormone (α-MSH) is suppressed. To investigate whether pregnancy is associated with changes in the response of hypothalamic α-MSH target neurons, non-pregnant and pregnant rats were treated with α-MSH or vehicle and c-fos expression in hypothalamic nuclei was then examined. Furthermore, the firing rate of supraoptic nucleus (SON) oxytocin neurons, a known α-MSH responsive neuronal population, was examined in non-pregnant and pregnant rats following α-MSH treatment. Intracerebroventricular injection of α-MSH significantly increased the number of c-fos-positive cells in the paraventricular, arcuate and ventromedial hypothalamic nuclei in non-pregnant rats, but no significant increase was observed in any of these regions in pregnant rats. In the SON, α-MSH did induce expression of c-fos during pregnancy, but this was significantly reduced compared to that observed in the non-pregnant group. Furthermore, during pregnancy, SON oxytocin neurons did not demonstrate the characteristic α-MSH-induced inhibition of firing rate that was observed in non-pregnant animals. Melanocortin receptor mRNA levels during pregnancy were similar to non-pregnant animals, suggesting that receptor down-regulation is unlikely to be a mechanism underlying the attenuated responses to α-MSH during pregnancy. Given the known functions of α-MSH in the hypothalamus, the attenuated responses will facilitate adaptive changes in appetite regulation and oxytocin secretion during pregnancy.

Reproductive Regulation of Gene Expression in the Hypothalamic Supraoptic and Paraventricular Nuclei

“…Hence, the reduced Fos expression might reflect changes in regulation by other neurotransmitters (e.g. we have recently found reduced α‐melanocyte‐stimulating hormone‐induced Fos expression in the supraoptic and paraventricular nuclei during pregnancy) .…”

Central Effects of Leptin on Glucose Homeostasis are Modified during Pregnancy in the Rat

“…Furthermore, MTII injected directly into the paraventricular nucleus of the hypothalamus leads to impaired glucose tolerance in female mice . Given that pregnant rats are insensitive to the satiety effects of α‐MSH and show an attenuated cellular response to α‐MSH in the hypothalamus, as measured by α‐MSH‐induced c‐fos expression , it is likely that the melanocortin pathway may also underlie at least part of the insensitivity to the effects of leptin on glucose homeostasis during pregnancy.…”

Oxytocin – The Sweet Hormone?

“…The inhibition of electrical activity is the consequence of evoked production of endocannabinoids, which act on afferent inputs to the SON, suppressing the release of excitatory transmitters from afferent endings that express cannabinoid receptors. Interestingly, in pregnant rats α-MSH has no effect on oxytocin neurons [50], and while icv α-MSH increases c-fos expression in the PVN, SON, arcuate nucleus, and ventromedial nucleus of the hypothalamus (VMN) in non-pregnant rats, this response is also suppressed in pregnant rats [50]. How this change arises is not known, as the hypothalamic levels of mRNA expression of MC3 and MC4 receptors are unchanged in pregnancy, but it may contribute to the hyperphagia of late pregnancy.…”