Butyrate increases intracellular calcium levels and enhances growth hormone release from rat anterior pituitary cells via the G-protein-coupled receptors GPR41 and 43.

Maria Consolata Miletta,Christa E Flück,Andrée Eblé,Roland A Ammann,Primus-E Mullis,Vibor Petkovic

doi:10.1371/journal.pone.0107388

Maria Consolata Miletta, Christa E Flück + Show 4 more

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https://doi.org/10.1371/journal.pone.0107388

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Abstract

Butyrate is a short-chain fatty acid (SCFA) closely related to the ketone body ß-hydroxybutyrate (BHB), which is considered to be the major energy substrate during prolonged exercise or starvation. During fasting, serum growth hormone (GH) rises concomitantly with the accumulation of BHB and butyrate. Interactions between GH, ketone bodies and SCFA during the metabolic adaptation to fasting have been poorly investigated to date. In this study, we examined the effect of butyrate, an endogenous agonist for the two G-protein-coupled receptors (GPCR), GPR41 and 43, on non-stimulated and GH-releasing hormone (GHRH)-stimulated hGH secretion. Furthermore, we investigated the potential role of GPR41 and 43 on the generation of butyrate-induced intracellular Ca2+ signal and its ultimate impact on hGH secretion. To study this, wt-hGH was transfected into a rat pituitary tumour cell line stably expressing the human GHRH receptor. Treatment with butyrate promoted hGH synthesis and improved basal and GHRH-induced hGH-secretion. By acting through GPR41 and 43, butyrate enhanced intracellular free cytosolic Ca2+. Gene-specific silencing of these receptors led to a partial inhibition of the butyrate-induced intracellular Ca2+ rise resulting in a decrease of hGH secretion. This study suggests that butyrate is a metabolic intermediary, which contributes to the secretion and, therefore, to the metabolic actions of GH during fasting.

Highlights

Growth hormone (GH) is a member of the somatotropin/ prolactin family of hormones and it is secreted in a pulsatile manner by the pituitary gland
Butyrate treatment itself significantly increased hGH secretion (p,0.01) compared to the basal level while in the presence of both growth hormone releasing hormone (GHRH) and butyrate, extracellular GH secretion was significantly increased (p,0.01) when compared to cells stimulated with butyrate only (Fig. 1B)
Our results indicate that the reduction in cAMP level induced by co-treatment with GHRH and butyrate may occur as a result of an interaction between different Ga subunits associated with either GPR41 (Gi/o inhibiting the cAMP production) or GHRHR (Gs catalysing the increase in cAMP levels), which are activated by butyrate or by GHRH

Summary

Introduction

Growth hormone (GH) is a member of the somatotropin/ prolactin family of hormones and it is secreted in a pulsatile manner by the pituitary gland. Potential secondary mediators that contribute to the metabolic action of GH during fasting have not been investigated in great detail. During fasting when the liver switches to fatty acid oxidation, a rise in serum GH is observed together with the accumulation of BHB and SCFA such as acetate, propionate and butyrate. The regulation of GH release was believed to represent the net result of the antagonistic actions of hypothalamic growth hormone releasing hormone (GHRH) and somatostatin (SRIF) on the pituitary, as well as negative feedback via circulating insulin-like growth factor I (IGF-I) [8]. The effect of butyrate and BHB on GH secretion is poorly investigated and it remains unclear whether butyrate induces GH secretion by a direct action on somatotroph cells of the pituitary gland

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