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Pharmacological approaches to increase GH levels in obese individuals by GH injection or GH\u2010releasing hormone receptor agonist showed promising effects on fat reduction. However, side effects on glucose metabolism and the heavy costs on making large peptides hindered their clinical application. Here, we tested whether stimulation of endogenous GH secretion by a synthetic GH secretagogue receptor (GHSR) agonist, hexarelin, improved the metabolism in a hyperphagic obese mouse model. Male melanocortin 4 receptor knockout mice (MC4RKO) were pair\u2010fed and received continuous hexarelin (10.56\u00a0\u03bcg\/day) or vehicle infusion by an osmotic pump for 3\u20104\u00a0weeks. Hexarelin treatment significantly increased the pulsatile GH secretion without detectable alteration on basal GH secretion in MC4RKO mice. The treated mice showed increased lipolysis and lipid oxidation in the adipose tissue, and reduced de novo lipogenesis in the liver, leading to reduced visceral fat mass, reduced triglyceride content in liver, and unchanged circulating free fatty acid levels. Importantly, hexarelin treatment improved the whole\u2010body insulin sensitivity but did not alter glucose tolerance, insulin levels, or insulin\u2010like growth factor 1 (IGF\u20101) levels. The metabolic effects of hexarelin were likely through the direct action of GH, as indicated by the increased expression level of genes involved in GH signaling pathways in visceral adipose tissues and liver. In conclusion, hexarelin treatment stimulated the pulsatile GH secretion and reduced the fat accumulation in visceral depots and liver in obese MC4RKO mice with improved insulin sensitivity without altered levels of insulin or IGF\u20101. It provides evidence for managing obesity by enhancing pulsatile GH secretion through activation of GHSR in the pituitary gland.<\/jats:p>","DOI":"10.1096\/fj.202001924rr","type":"journal-article","created":{"date-parts":[[2020,12,25]],"date-time":"2020-12-25T05:04:07Z","timestamp":1608872647000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Stimulation of endogenous pulsatile growth hormone secretion by activation of growth hormone secretagogue receptor reduces the fat accumulation and improves the insulin sensitivity in obese mice"],"prefix":"10.1096","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1194-2701","authenticated-orcid":false,"given":"Zhengxiang","family":"Huang","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences University of Queensland St Lucia QLD 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