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Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice.

ABSTRACT: Ghrelin, an octanoylated peptide hormone produced in the stomach, rises dramatically in mouse plasma during chronic severe calorie deprivation, an event that is essential to maintain life. The mechanism for this increase is not understood. Here, we study the control of ghrelin secretion in tissue culture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T-antigen transgene. We found that the ghrelin-secreting cells express high levels of mRNA encoding beta(1)-adrenergic receptors. Addition of norepinephrine or epinephrine to the culture medium stimulated ghrelin secretion, and this effect was blocked by atenolol, a selective beta(1)-adrenergic antagonist. When WT mice were treated with reserpine to deplete adrenergic neurotransmitters from sympathetic neurons, the fasting-induced increase in plasma ghrelin was blocked. Inhibition was also seen following atenolol administration. We conclude that ghrelin secretion during fasting is induced by adrenergic agents released by sympathetic neurons and acting directly on beta(1) receptors on the ghrelin-secreting cells of the stomach.

SUBMITTER: Zhao TJ

PROVIDER: S-EPMC2936616 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice.

Zhao Tong-Jin TJ Sakata Ichiro I Li Robert Lin RL Liang Guosheng G Richardson James A JA Brown Michael S MS Goldstein Joseph L JL Zigman Jeffrey M JM

Proceedings of the National Academy of Sciences of the United States of America 20100816 36

Ghrelin, an octanoylated peptide hormone produced in the stomach, rises dramatically in mouse plasma during chronic severe calorie deprivation, an event that is essential to maintain life. The mechanism for this increase is not understood. Here, we study the control of ghrelin secretion in tissue culture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T-antigen transgene. We found that the ghrelin-secreting cells express high levels of mRNA encoding beta(1)-adrenerg ...[more]

PMID: 20713709

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Project description:ContextGlucagon-like peptide 1 (GLP-1), an insulinotropic peptide released into the circulation from intestinal enteroendocrine cells, is considered a hormonal mediator of insulin secretion. However, the physiological actions of circulating GLP-1 have been questioned because of the short half-life of the active peptide. Moreover, there is mounting evidence for localized, intra-islet mediation of GLP-1 receptor (GLP-1r) signaling including a role for islet dipeptidyl-peptidase 4 (DPP4).ObjectiveTo determine whether GLP-1r signaling contributes to insulin secretion in the absence of enteral stimulation and increased plasma levels, and whether this is affected by DPP4.MethodsSingle-site study conducted at an academic medical center of 20 nondiabetic subjects and 13 subjects with type 2 diabetes. This was a crossover study in which subjects received either a DPP4 inhibitor (DPP4i; sitagliptin) or placebo on 2 separate days. On each day they received a bolus of intravenous (IV) arginine during sequential 60-minute infusions of the GLP-1r blocker exendin[9-39] (Ex-9) and saline. The main outcome measures were arginine-stimulated secretion of C-Peptide (C-PArg) and insulin (InsArg).ResultsPlasma GLP-1 remained at fasting levels throughout the experiments and IV arginine stimulated both α- and β-cell secretion in all subjects. Ex-9 infusion reduced C-PArg in both the diabetic and nondiabetic groups by ~14% (P < .03 for both groups). Sitagliptin lowered baseline glycemia but did not affect the primary measures of insulin secretion. However, a significant interaction between sitagliptin and Ex-9 suggested more GLP-1r activation with DPP4i treatment in subjects with diabetes.ConclusionGLP-1r activation contributes to β-cell secretion in diabetic and nondiabetic people during α-cell activation, but in the absence of increased circulating GLP-1. These results are compatible with regulation of β-cells by paracrine signals from α-cells. This process may be affected by DPP4 inhibition.

Project description:The inhibition of insulin-stimulated glucose transport by isoprenaline, a mixed beta-adrenergic-receptor (AR) agonist, is well documented in rat adipocytes. Since it has been described that rat adipocytes possess not only beta 1- and beta 2- but also beta 3-ARs, the influence of various subtype-selective beta-AR agonists and antagonists on 2-deoxyglucose (2-DG) transport was assessed in order to characterize the beta-AR subtype involved in the adrenergic counter-regulation of the insulin effect. The stimulation of 2-DG transport by insulin was counteracted, in a dose-dependent manner, by all the beta-AR agonists tested, and the magnitude of the inhibition followed the rank order: BRL 37344 > isoprenaline = noradrenaline >> dobutamine = procaterol. The same rank order of potency was obtained for lipolysis activation. This is not in accordance with the pharmacological definition of a beta 1- or a beta 2-adrenergic effect, but agrees with the pharmacological pattern of a beta 3-adrenergic effect. The inhibitory effect of the beta 3-agonist BRL 37344 on insulin-stimulated 2-DG transport was not reversed by either the selective beta 1-antagonist ICI 89406 or the beta 2-antagonist ICI 118551. In addition, neither of these beta-antagonists was able to block the isoprenaline and noradrenaline effects, supporting major beta 3-adrenoceptor-subtype involvement in the adrenergic inhibition of insulin-stimulated 2-DG transport. Like isoprenaline, BRL 37344 inhibited (60% inhibition) insulin-stimulated glucose transport only when adenosine deaminase was present in the assay. Furthermore, the maximal inhibitory effects of isoprenaline and BRL 37344 were not additive, and were both dependent on albumin concentration in the incubation medium: they increased when the albumin concentration decreased in the medium from 3.5 to 1%. To conclude, the similarities between isoprenaline and BRL 37344 action on insulin-stimulated 2-DG transport, the poor efficacy of the beta 1-/beta 2-agonists and the lack of effect of selective beta 1- and beta 2-antagonists are compelling arguments to support the important role of beta 3-adrenoceptors in the adrenergic inhibition of glucose transport in rat adipocytes.

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Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice.

Publications

Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice.

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