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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 September 1, 2016; First published August 22, 2016
Citation Information: J Clin Invest. 2016;126(9):3467-3478. https://doi.org/10.1172/JCI86270.
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Categories: Research Article Endocrinology

β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals

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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 1

Generation of conditional β1AR-KO mice and mice with ghrelin cell–selective β1AR deletion.

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Generation of conditional β1AR-KO mice and mice with ghrelin cell–select...
Schematic diagrams show the homologous recombination targeting strategy to flank the β1AR (Adrb1) coding region with loxP sites, thus creating conditional β1AR-KO mice. Binding sites for Southern blot probes used to detect correctly targeted genomic DNA (after restriction digestion with Sph1) are depicted. Crosses first with Flp1 recombinase mice to remove the frt-Neo-frt cassette that had been included in the targeting construct to find neomycin-resistant ES cell clones and then with ghrelin-Cre mice result in Cre recombinase–mediated removal of the β1AR coding sequence selectively in ghrelin cells.
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