TY - JOUR
T1 - B1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals
AU - Mani, Bharath K.
AU - Osborne-Lawrence, Sherri
AU - Vijayaraghavan, Prasanna
AU - Hepler, Chelsea
AU - Zigman, Jeffrey M.
N1 - Funding Information:
This work was supported by the NIH (R01 DK103884); an International Research Alliance with the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen; the Diana and Richard C. Strauss Professorship in Biomedical Research; the Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine (to JMZ); and the Hilda and Preston Davis Foundation Postdoctoral Fellowship Program in Eating Disorders Research (to BKM). We thank the members of the Molecular Pathology Core facility, the Flow Cytometry Core facility, the Transgenic Core facility and the Animal Resource Center at UT Southwestern Medical Center for their exceptional service and support. Catecholamine assays were performed by the Vanderbilt University Medical Center (VUMC) Hormone Assay and Analytical Services Core (supported by NIH grants DK059637 and DK020593)
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI86270
DO - 10.1172/JCI86270
M3 - Article
C2 - 27548523
AN - SCOPUS:84987850196
SN - 0021-9738
VL - 126
SP - 3467
EP - 3478
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 9
ER -