α-Melanocyte-Stimulating Hormone Is Contained in Nerve Terminals Innervating Thyrotropin-Releasing Hormone-Synthesizing Neurons in the Hypothalamic Paraventricular Nucleus and Prevents Fasting-Induced Suppression of Prothyrotropin-Releasing Hormone Gene Expression

Abstract

The hypothalamic arcuate nucleus has an essential role in mediating the homeostatic responses of the thyroid axis to fasting by altering the sensitivity of prothyrotropin-releasing hormone (pro-TRH) gene expression in the paraventricular nucleus (PVN) to feedback regulation by thyroid hormone. Because agouti-related protein (AGRP), a leptin-regulated, arcuate nucleus-derived peptide with ␣-MSH antagonist activity, is contained in axon terminals that terminate on TRH neurons in the PVN, we raised the possibility that ␣-MSH may also participate in the mechanism by which leptin influences pro-TRH gene expression. By double-labeling immunocytochemistry, ␣-MSH-IR axon varicosities were juxtaposed to ϳ70% of pro-TRH neurons in the anterior and periventricular parvocellular subdivisions of the PVN and to 34% of pro-TRH neurons in the medial parvocellular subdivision, establishing synaptic contacts both on the cell soma and dendrites. All pro-TRH neurons receiving contacts by ␣-MSH-containing fibers also were innervated by axons containing AGRP. The intracerebroventricular infusion of 300 ng of ␣-MSH every 6 hr for 3 d prevented fasting-induced suppression of pro-TRH in the PVN but had no effect on AGRP mRNA in the arcuate nucleus. ␣-MSH also increased circulating levels of free thyroxine (T4) 2.5-fold over the levels in fasted controls, but free T4 did not reach the levels in fed controls. These data suggest that ␣-MSH has an important role in the activation of pro-TRH gene expression in hypophysiotropic neurons via either a mono-and/or multisynaptic pathway to the PVN, but factors in addition to ␣-MSH also contribute to the mechanism by which leptin administration restores thyroid hormone levels to normal in fasted animals.

Polymorphisms in the serotonin reuptake transporter gene modify the consequences of social status on metabolic health in female rhesus monkeys

“…Within s-variant females, dominant females had higher levels than subordinate animals. Thyroid hormones are reduced by hypercortisolism associated with chronic disease [75] as well as restraint stress [76] and food restriction [77,78], effects that may be mediated through a reduction in hypothalamic TRH expression. However, other data indicate this decrease induced by food restriction [47] and stress [48] may occur independent of changes in TRH expression.…”

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

“…MC4 receptors are critical for the inhibitory effects of AgRP on thyroid function, as the effects were not seen in MC4 receptor knockout mice (Fekete et al, 2004). Conversely, central injection of MC3 or MC4 receptor agonists such as α-MSH or a stable analog of α-MSH increased circulating TSH (Kim et al, 2000) or free T4 concentrations in fasting rodents, probably via direct actions which stimulate TRH expression and release in the PVN (Kim et al, 2000 andFekete et al, 2000). Further evidence for a physiological role of MC4 in the regulation of thyroid function is the recent in vivo discovery that thyroid hormones inhibit MC4 receptor expression in brain nuclei known to regulate thyroid function or energy homeostasis, namely the PVN, arcuate nucleus of the hypothalamus and brain stem, via their receptor interactions with thyroid hormone-response elements on the MC4 receptor gene ( Decherf et al, 2010).…”

The Neuroanatomical Axis for Control of Energy Balance

“…Reduction in leptin level has been implicated as a critical contributor to all neuroendocrine changes associated with fasting. Thus, the neuroendocrine effects of fasting are reversed by systemic administration of leptin that restores plasma leptin to prefasting levels (2,3,55,129,196). The assumption is that it is the hypothalamus that contains the Ob-Rb that triggers both the effects of deprivation (by reduced stimulation) and their reversal with exogenous leptin treatment.…”

“…The assumption appears sensible given identified circuits that link Ob-Rb in the hypothalamus and activity of PVN neurons. For example, Ob-Rb-bearing POMC neurons in the arcuate nucleus that project to TRH-containing cells of the PVN have been implicated in leptin's effect on thyroid secretion (3,55,109). The possibility that leptin receptors in the caudal brainstem contribute to the modulation of endocrine output by fasting was addressed recently by Zhou and Schneider (210), who showed that fasting-induced anestrus was prevented by leptin delivery to the fourth ventricle.…”