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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Research Article Endocrinology

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 2

Ghrelin cell–selective β1AR deletion reduces plasma ghrelin, resulting in fasting hypoglycemia.

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Ghrelin cell–selective β1AR deletion reduces plasma ghrelin, resulting i...
Plasma acyl- and total ghrelin levels in ad libitum–fed (A and B, respectively) and 24-hour–fasted conditions (D and E, respectively) in 8-week-old male mice and their corresponding blood glucose levels (C and F, respectively). n = 19–30. *P < 0.05 and ****P < 0.001, for significant reductions in plasma ghrelin or blood glucose in GC-β1AR–/– mice compared with control groups by 1-way ANOVA, followed by Holm-Sidak’s post-hoc multiple comparisons test. (G) Acyl-ghrelin concentrations in media from primary gastric mucosal cell cultures derived from ad libitum–fed control groups or GC-β1AR–/– mice treated for 6 hours with or without 10 μM norepinephrine (NE). n = 6–9 wells each. *P < 0.05 and ****P < 0.001, for significant increases in ghrelin secretion with norepinephrine treatment compared with vehicle treatment within the same genotype and significant decreases in ghrelin secretion in cultures from GC-β1AR–/– mice compared with control groups, as analyzed by 2-way ANOVA, followed by Holm-Sidak’s post-hoc multiple comparisons test. All values are expressed as the mean ± SEM. w/w, mice with WT β1AR genes; fl/fl, mice homozygous for the loxP-flanked β1AR gene; –, absence of the ghrelin-Cre Tg; +, presence of the ghrelin-Cre Tg.