Disrupting the ghrelin-growth hormone axis limits ghrelin's orexigenic but not glucoregulatory actions.
Disrupting the ghrelin-growth hormone axis limits ghrelin's orexigenic but not glucoregulatory actions.
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DOI：
10.1016/j.molmet.2021.101258
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发表时间：
2021-11
影响因子：
8.1
通讯作者：
Zigman JM
中科院分区：
文献类型：
--
作者：
Gupta D;Patterson AM;Osborne-Lawrence S;Bookout AL;Varshney S;Shankar K;Singh O;Metzger NP;Richard CP;Wyler SC;Elmquist JK;Zigman JM
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. 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.
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DOI：
10.1126/science.1196154
发表时间：
2010-12-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Barnett BP;Hwang Y;Taylor MS;Kirchner H;Pfluger PT;Bernard V;Lin YY;Bowers EM;Mukherjee C;Song WJ;Longo PA;Leahy DJ;Hussain MA;Tschöp MH;Boeke JD;Cole PA
通讯作者：
Cole PA
DOI：
10.1073/pnas.1901867116
发表时间：
2019-04-09
影响因子：
11.1
作者：
Fang, Fei;Shi, Xuanming;Liang, Guosheng
通讯作者：
Liang, Guosheng
影响因子：
29.4
作者：
Date, Y;Murakami, N;Nakazato, M
通讯作者：
Nakazato, M
影响因子：
15.9
作者：
Chuang, Jen-Chieh;Perello, Mario;Zigman, Jeffrey M.
通讯作者：
Zigman, Jeffrey M.
影响因子：
15.9
作者：
Abizaid, Alfonso;Liu, Zhong-Wu;Horvath, Tamas L.
通讯作者：
Horvath, Tamas L.