| Autor: |
Shankar K; Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA., Takemi S; Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.; Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Sakuraku, Saitama, Japan., Gupta D; Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA., Varshney S; Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA., Mani BK; Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA., Osborne-Lawrence S; Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA., Metzger NP; Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA., Richard CP; Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA., Berglund ED; Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA., Zigman JM; Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.; Division of Endocrinology, Department of Internal Medicine, and.; Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas, USA. |
| Abstrakt: |
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. |
