Disrupting the ghrelin-growth hormone axis limits ghrelin's orexigenic but not glucoregulatory actions

• Published in: Molecular metabolism (Germany) Vol. 53; p. 101258
• Main Authors: Gupta, Deepali, Patterson, Anna M., Osborne-Lawrence, Sherri, Bookout, Angie L., Varshney, Salil, Shankar, Kripa, Singh, Omprakash, Metzger, Nathan P., Richard, Corine P., Wyler, Steven C., Elmquist, Joel K., Zigman, Jeffrey M.
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.11.2021; Elsevier
• Subjects: Animals; Blood Glucose - metabolism; Ghrelin; Ghrelin - analogs & derivatives; Ghrelin - metabolism; GHSR; Growth hormone; Growth Hormone - metabolism; Mice; Original; Pituitary; Receptors, Ghrelin - deficiency; Receptors, Ghrelin - genetics; Receptors, Ghrelin - metabolism; Somatotroph; GHSR; Growth hormone; Ghrelin; Pituitary; Somatotroph
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2021.101258

Acyl-ghrelin regulates eating, body weight, blood glucose, and GH secretion upon binding to its receptor GHSR (growth hormone secretagogue receptor; ghrelin receptor). GHSR is distributed in several brain regions and some peripheral cell-types including pituitary somatotrophs. The objective of the current study was to determine the functional significance of acyl-ghrelin's action on GHSR-expressing somatotrophs in mediating GH secretion and several of acyl-ghrelin's metabolic actions. GH-IRES-Cre mice and loxP-flanked (floxed) GHSR mice were newly developed and then crossed to one another to generate mice that lacked GHSR selectively from somatotrophs. Following validation of mice with somatotroph-selective GHSR deletion, metabolic responses of these mice and control littermates were assessed following both acute and chronic acyl-ghrelin administration, a 24-h fast, and a prolonged 60% chronic caloric restriction protocol modeling starvation. In mice with somatotroph-selective GHSR deletion, a single peripheral injection of acyl-ghrelin failed to induce GH secretion or increase food intake, unlike wild-type and other littermate control groups. However, the usual acute blood glucose increase in response to the acyl-ghrelin bolus was preserved. Similarly, chronic s.c. acyl-ghrelin administration to mice with somatotroph-selective GHSR deletion failed to increase plasma GH, food intake, or body weight. Physiologically elevating plasma acyl-ghrelin via a 24-h fast also failed to raise plasma GH and resulted in a limited hyperphagic response upon food reintroduction in mice with somatotroph-selective GHSR deletion, although those mice nonetheless did not exhibit an exaggerated reduction in blood glucose. Physiologically elevating plasma acyl-ghrelin via a 15-day caloric restriction protocol which provided only 40% of usual daily calories failed to raise plasma GH in mice with somatotroph-selective GHSR deletion, although those mice did not exhibit life-threatening hypoglycemia. These results reveal that direct engagement of GHSR-expressing somatotrophs is required for a peripheral ghrelin bolus to acutely stimulate GH secretion and the actions of chronic acyl-ghrelin delivery and physiological plasma acyl-ghrelin elevations to increase plasma GH. These results also suggest that actions of acyl-ghrelin to increase food intake and body weight are reliant on direct activation of GHSRs expressed on somatotrophs. Furthermore, these results suggest that the glucoregulatory actions of acyl-ghrelin – in particular, its actions to raise blood glucose when acutely administered, prevent small blood glucose drops following a 24-h fast, and avert life-threatening hypoglycemia during an acute-on-chronic caloric restriction protocol – do not depend on GHSR expression by somatotrophs. [Display omitted] •Mice with pituitary somatotroph-selective GHSR deletion were generated.•Somatotroph-expressed GHSRs mediate GH secretion and food intake after acute ghrelin.•Body weight effects of chronic ghrelin infusion require somatotroph-expressed GHSRs.•Somatotroph-expressed GHSRs enable GH to increase upon chronic caloric restriction.•Mice lacking somatotroph GHSRs maintain euglycemia upon chronic caloric restriction.