Absence of TRH Receptor 1 in Male Mice Affects Gastric Ghrelin Production

Abstract

TRH not only functions as a thyrotropin releasing hormone but also acts as a neuropeptide in central circuits regulating food intake and energy expenditure. As one suggested mode of action, TRH expressed in the caudal brainstem influences vagal activity by activating TRH receptor 1 (TRH-R1). In order to evaluate the impact of a diminished medullary TRH signaling on ghrelin metabolism, we analyzed metabolic changes of TRH-R1 knockout (R1ko) mice in response to 24 hours of food deprivation. Because R1ko mice are hypothyroid, we also studied eu- and hypothyroid wild-type (wt) animals and R1ko mice rendered euthyroid by thyroid hormone treatment. Independent of their thyroidal state, R1ko mice displayed a higher body weight loss than wt animals and a delayed reduction in locomotor activity upon fasting. Ghrelin transcript levels in the stomach as well as total ghrelin levels in the circulation were equally high in fasted wt and R1ko mice. In contrast, only wt mice responded to fasting with a rise in ghrelin-O-acyltransferase mRNA expression and consequently an increase in serum levels of acylated ghrelin. Together, our data suggest that an up-regulation of medullary TRH expression and subsequently enhanced activation of TRH-R1 in the vagal system represents a critical step in the stimulation of ghrelin-O-acyltransferase expression upon starvation that in turn is important for adjusting the circulating levels of acylated ghrelin to the fasting condition.

The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation

“…For example, mice with TRH deficiency are hyperglycaemic, due to an impaired insulin response to glucose (Yamada et al, 1997 ). Reduced TRH signaling also impedes leptin production and ghrelin acylation, which results in less energy conservation during fasting and a lower body mass in the non-pregnant state (Groba et al, 2013 ; Mayerl et al, 2015 ). Investigations are warranted to identify whether TRH may contribute to the regulation of glucose handling and appetite in the mother during pregnancy.…”

Thyrotropin Releasing Hormone and Food-Intake in Mammals: An Update

“…Because of the lack of specific TRH receptor antagonists, the relevance of TRH receptors for TRH effect on food-intake could be inferred from the use of neutralizing receptor antibodies, antisense tools, the phenotype of mouse knockout (KO) for each receptor, or genome-wide association studies (GWAS). Mice KO for Trhr have low serum TH concentrations and mild hyperglycemia [124,125], but daily food-intake in 3-4 months old animals is not altered if normalized to body weight and even if the animals are made euthyroid [126,127]. While in euthyroid ob/ob mice, leptin injection twice daily for 3 consecutive days powerfully reduces food-intake, it does it less conspicuously in hypothyroid Trhr/ob double KO as well as in 2-mercapto-1-methylimidazole-, sodium perchlorate-treated ob/ob mice, suggesting that food-intake in response to leptin depends on thyroid status, but not on TRH-R1 signaling [126].…”

“…While in euthyroid ob/ob mice, leptin injection twice daily for 3 consecutive days powerfully reduces food-intake, it does it less conspicuously in hypothyroid Trhr/ob double KO as well as in 2-mercapto-1-methylimidazole-, sodium perchlorate-treated ob/ob mice, suggesting that food-intake in response to leptin depends on thyroid status, but not on TRH-R1 signaling [126]. In fasted Trhr KO mice, increases in stomach ghrelin-O-acyltransferase (GOAT) expression and acyl-ghrelin serum concentration are blunted independent of the thyroid state, suggesting TRH-R1 regulates GOAT expression, and thus the concentration of acylated ghrelin in the circulation [127]. Since acylated ghrelin exerts a strong orexigenic effect by activating NPY/AgRP ARC neurons [128,129], these data suggest that TRH-R1 is implicated in a circuit relevant for food-intake (see section 4.2.3).…”

“…The physiological significance of this projection has been reviewed [15]. Briefly, TRH neurons located in the raphe pallidus, raphe obscurus, and parapyramidal regions [127,179] innervate neurons of the DMV [180], synapsing on DMV neurons that contribute vagal efferent innervation of the stomach [181,182]. In the DMV, Trhr is expressed abundantly in the medial column, which contains neurons that innervate the stomach [81,183,184].…”

Alpha-Melanocyte-Stimulating Hormone-Mediated Appetite Regulation in the Central Nervous System

“…TRH Neurons TRH was characterized based on its function as a releasing hormone involved in the regulation of the hypothalamic-pituitary-thyroid axis [126], but then it was found to act as a neuropeptide in central circuits regulating food intake and energy expenditure [127]. TRH can regulate energy homeostasis through the effects on thyroid function orchestrated through hypophysiotropic neurons in the PVN, or central effects on feeding behavior, thermogenesis, locomotor activation, and autonomic regulation [128,129].…”