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Ghrelin cell–expressed insulin receptors mediate meal- and obesity-induced declines in plasma ghrelin
Kripa Shankar, … , Eric D. Berglund, Jeffrey M. Zigman
Kripa Shankar, … , Eric D. Berglund, Jeffrey M. Zigman
Published September 2, 2021
Citation Information: JCI Insight. 2021;6(18):e146983. https://doi.org/10.1172/jci.insight.146983.
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Research Article Endocrinology Metabolism

Ghrelin cell–expressed insulin receptors mediate meal- and obesity-induced declines in plasma ghrelin

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Abstract

Mechanisms underlying postprandial and obesity-associated plasma ghrelin reductions are incompletely understood. Here, using ghrelin cell–selective insulin receptor–KO (GhIRKO) mice, we tested the impact of insulin, acting via ghrelin cell–expressed insulin receptors (IRs), to suppress ghrelin secretion. Insulin reduced ghrelin secretion from cultured gastric mucosal cells of control mice but not from those of GhIRKO mice. Acute insulin challenge and insulin infusion during both hyperinsulinemic-hypoglycemic clamps and hyperinsulinemic-euglycemic clamps lowered plasma ghrelin in control mice but not GhIRKO mice. Thus, ghrelin cell–expressed IRs are required for insulin-mediated reductions in plasma ghrelin. Furthermore, interventions that naturally raise insulin (glucose gavage, refeeding following fasting, and chronic high-fat diet) also lowered plasma ghrelin only in control mice — not GhIRKO mice. Thus, meal- and obesity-associated increases in insulin, acting via ghrelin cell–expressed IRs, represent a major, direct negative modulator of ghrelin secretion in vivo, as opposed to ingested or metabolized macronutrients. Refed GhIRKO mice exhibited reduced plasma insulin, highlighting ghrelin’s actions to inhibit insulin release via a feedback loop. Moreover, GhIRKO mice required reduced glucose infusion rates during hyperinsulinemic-hypoglycemic clamps, suggesting that suppressed ghrelin release resulting from direct insulin action on ghrelin cells usually limits ghrelin’s full potential to protect against insulin-induced hypoglycemia.

Authors

Kripa Shankar, Shota Takemi, Deepali Gupta, Salil Varshney, Bharath K. Mani, Sherri Osborne-Lawrence, Nathan P. Metzger, Corine P. Richard, Eric D. Berglund, Jeffrey M. Zigman

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Figure 1

Validation of ghrelin cell–selective deletion of IR gene expression in GhIRKO mice.

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Validation of ghrelin cell–selective deletion of IR gene expression in G...
(A) IR mRNA expression in FACS-purified gastric mucosal ghrelin cells (Tom+) and nonghrelin gastric mucosal cells (Tom–) obtained from IRfl/fl/GCreTg+ (GhIRKO) mice and IRwt/wt/GCreTg+ control mice on a tdTomato reporter background, as determined by qPCR. Data are expressed as ΔΔCt values relative to those in Tom– cells from IRwt/wt/GcreTg+ control mice. n = 2–3 independent sorting by FACS (with each FACS sort containing pooled cells from 3 mouse stomachs of the same genotype). (B) Ghrelin levels in media from primary gastric mucosal cell cultures derived from ad libitum–fed control groups or GhIRKO mice treated for 6 hours with or without 1 nM insulin. n = 6–9 wells each. Data are presented as mean ± SEM. Data were calculated using repeated measures 2-way ANOVA, followed by a Sidak’s post hoc multiple-comparison test. *P < 0.05.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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