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The ghrelin receptor, also known as growth hormone secretagogue receptor (<jats:styled-content style=\"fixed-case\">GHS<\/jats:styled-content>\u2010R), is highly expressed in the brain, with the highest expression in agouti\u2010related peptide (Ag<jats:styled-content style=\"fixed-case\">RP<\/jats:styled-content>) neurones in the hypothalamus. Compelling evidence indicates that ghrelin serves as a survival hormone with respect to maintaining blood glucose and body weight during nutritional deficiencies. Recent studies have demonstrated that Ag<jats:styled-content style=\"fixed-case\">RP<\/jats:styled-content> neurones are involved in metabolic and behavioural adaptation to an energy deficit to improve survival. In the present study, we used a neuronal subtype\u2010specific <jats:styled-content style=\"fixed-case\">GHS<\/jats:styled-content>\u2010R knockout mouse (<jats:italic>AgRP\u2010Cre;Ghsr<\/jats:italic><jats:sup><jats:italic>f\/f<\/jats:italic><\/jats:sup>) to investigate the role of <jats:styled-content style=\"fixed-case\">GHS<\/jats:styled-content>\u2010R in hypothalamic Ag<jats:styled-content style=\"fixed-case\">RP<\/jats:styled-content> neurones in metabolic and behavioural adaptation to hypocaloric restricted feeding. We subjected the mice to a restricted feeding regimen of 40% mild calorie restriction (<jats:styled-content style=\"fixed-case\">CR<\/jats:styled-content>), with one\u2010quarter of food allotment given in the beginning of the light cycle and three\u2010quarters given at the beginning of the dark cycle, to mimic normal mouse intake pattern. The <jats:styled-content style=\"fixed-case\">CR<\/jats:styled-content>\u2010fed <jats:italic>AgRP\u2010Cre;Ghsr<\/jats:italic><jats:sup><jats:italic>f\/f<\/jats:italic><\/jats:sup> mice exhibited reductions in body weight, fat mass and blood glucose. Metabolic profiling of these <jats:styled-content style=\"fixed-case\">CR<\/jats:styled-content>\u2010fed <jats:italic>AgRP\u2010Cre;Ghsr<\/jats:italic><jats:sup><jats:italic>f\/f<\/jats:italic><\/jats:sup> mice showed a trend toward reduced basal metabolic rate, significantly reduced core body temperature and a decreased expression of thermogenic genes in brown adipose tissue. This suggests a metabolic reset to a lower threshold. Significantly increased physical activity, a trend toward increased food anticipatory behaviour and altered fuel preferences were also observed in these mice. In addition, these <jats:styled-content style=\"fixed-case\">CR<\/jats:styled-content>\u2010fed <jats:italic>AgRP\u2010Cre;Ghsr<\/jats:italic><jats:sup><jats:italic>f\/f<\/jats:italic><\/jats:sup> mice exhibited a decreased counter\u2010regulatory response, showing impaired hepatic glucose production. Lastly, hypothalamic gene expression in <jats:italic>AgRP\u2010Cre;Ghsr<\/jats:italic><jats:sup><jats:italic>f\/f<\/jats:italic><\/jats:sup> mice revealed increased Ag<jats:styled-content style=\"fixed-case\">RP<\/jats:styled-content> expression and a decreased expression of genes in \u03b2\u2010oxidation pathways. In summary, our data suggest that <jats:styled-content style=\"fixed-case\">GHS<\/jats:styled-content>\u2010R in Ag<jats:styled-content style=\"fixed-case\">RP<\/jats:styled-content> neurones is a key component of the neurocircuitry involved in metabolic adaptation to calorie restriction.<\/jats:p>","DOI":"10.1111\/jne.12763","type":"journal-article","created":{"date-parts":[[2019,6,28]],"date-time":"2019-06-28T16:18:25Z","timestamp":1561738705000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Ghrelin receptor in agouti\u2010related peptide neurones regulates metabolic adaptation to calorie restriction"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6034-939X","authenticated-orcid":false,"given":"Chia\u2010Shan","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Science Texas A &amp;M University College Station TX USA"},{"name":"USDA\/ARS Children's Nutrition Research Center Department of Pediatrics Baylor College of Medicine Houston TX  USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odelia Y. 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