β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals
Bharath K. Mani, … , Chelsea Hepler, Jeffrey M. Zigman
Bharath K. Mani, … , Chelsea Hepler, Jeffrey M. Zigman
Published August 22, 2016
Citation Information: J Clin Invest. 2016;126(9):3467-3478. https://doi.org/10.1172/JCI86270.
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β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals

Abstract

Ghrelin is an orexigenic gastric peptide hormone secreted when caloric intake is limited. Ghrelin also regulates blood glucose, as emphasized by the hypoglycemia that is induced by caloric restriction in mouse models of deficient ghrelin signaling. Here, we hypothesized that activation of β1-adrenergic receptors (β1ARs) localized to ghrelin cells is required for caloric restriction–associated ghrelin release and the ensuing protective glucoregulatory response. In mice lacking the β1AR specifically in ghrelin-expressing cells, ghrelin secretion was markedly blunted, resulting in profound hypoglycemia and prevalent mortality upon severe caloric restriction. Replacement of ghrelin blocked the effects of caloric restriction in β1AR-deficient mice. We also determined that treating calorically restricted juvenile WT mice with beta blockers led to reduced plasma ghrelin and hypoglycemia, the latter of which is similar to the life-threatening, fasting-induced hypoglycemia observed in infants treated with beta blockers. These findings highlight the critical functions of ghrelin in preventing hypoglycemia and promoting survival during severe caloric restriction and the requirement for ghrelin cell–expressed β1ARs in these processes. Moreover, these results indicate a potential role for ghrelin in mediating beta blocker–associated hypoglycemia in susceptible individuals, such as young children.

Authors

Bharath K. Mani, Sherri Osborne-Lawrence, Prasanna Vijayaraghavan, Chelsea Hepler, Jeffrey M. Zigman

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Figure 3

Ghrelin cell–selective β1AR deletion blocks HFD-induced reductions in ghrelin but does not alter BW or ad libitum food intake.

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Ghrelin cell–selective β1AR deletion blocks HFD-induced reductions in gh...
(A) Plasma acyl-ghrelin levels in female mice fasted for 24 hours after 16 weeks of exposure to standard chow or an HFD. n = 11–16. ***P < 0.005, for significant differences in plasma ghrelin in GC-β1AR–/– mice compared with control genotype mice fed the same diet; ###P < 0.005, for significant reductions in plasma acyl-ghrelin in mice fed an HFD compared with mice fed standard chow. No significant changes in plasma acyl-ghrelin in GC-β1AR–/– mice fed chow or an HFD were observed. Data were analyzed by 2-way ANOVA, followed by Holm-Sidak’s post-hoc multiple comparisons test. (B) Quantitative estimation of relative preproghrelin mRNA levels in gastric mucosal cells from ad libitum–fed and 24-hour–fasted mice after 16 weeks of exposure to standard chow. Data are expressed as ΔΔCt values relative to ad libitum–fed β1ARw/w/G-CreTg– control mice. n = 5–7. *P < 0.05, for significant differences in preproghrelin mRNA between fasted GC-β1AR–/– mice and fasted control genotypes. Data were analyzed by 2-way ANOVA, followed by Holm-Sidak’s post-hoc multiple comparisons test. (C and D) BW and (E and F) weekly food intake in mice fed standard chow or an HFD for 16 weeks. n = 11–16. No significant changes were observed among the groups fed the same diet, as analyzed by repeated-measures 2-way ANOVA. Values are expressed as the mean ± SEM.