TY - JOUR
T1 - Ghrelin cell–expressed insulin receptors mediate meal- And obesity-induced declines in plasma ghrelin
AU - Shankar, Kripa
AU - Takemi, Shota
AU - Gupta, Deepali
AU - Varshney, Salil
AU - Mani, Bharath K.
AU - Osborne-Lawrence, Sherri
AU - Metzger, Nathan P.
AU - Richard, Corine P.
AU - Berglund, Eric D.
AU - Zigman, Jeffrey M.
N1 - Publisher Copyright:
© 2021, Shankar et al
PY - 2021/9/22
Y1 - 2021/9/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85115919022&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85115919022&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.146983
DO - 10.1172/jci.insight.146983
M3 - Article
C2 - 34473648
AN - SCOPUS:85115919022
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 18
M1 - e146983
ER -