Obese individuals often show low growth hormone (GH) secretion, which leads to reduced lipid mobilization and further fat accumulation. Pharmacological approaches to increase GH levels in obese individuals by GH injection or GH‐releasing 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‐fed and received continuous hexarelin (10.56 μg/day) or vehicle infusion by an osmotic pump for 3‐4 weeks. 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‐body insulin sensitivity but did not alter glucose tolerance, insulin levels, or insulin‐like growth factor 1 (IGF‐1) 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‐1. It provides evidence for managing obesity by enhancing pulsatile GH secretion through activation of GHSR in the pituitary gland.

中文翻译：

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通过激活生长激素促分泌素受体刺激内源性搏动性生长激素分泌减少脂肪堆积并提高肥胖小鼠的胰岛素敏感性

肥胖个体通常表现出低生长激素 (GH) 分泌，这会导致脂质动员减少和进一步的脂肪堆积。通过 GH 注射或 GH 释放激素受体激动剂提高肥胖个体 GH 水平的药理学方法显示出有希望的减脂效果。然而，葡萄糖代谢的副作用和制造大肽的高昂成本阻碍了它们的临床应用。在这里，我们测试了合成的 GH 促分泌素受体 (GHSR) 激动剂 hexarelin 刺激内源性 GH 分泌是否改善了嗜食性肥胖小鼠模型的新陈代谢。雄性黑皮质素 4 受体敲除小鼠 (MC4RKO) 被配对喂养并接受连续的六瑞林 (10.56 μg/天) 或渗透泵的载体输注 3-4 周。Hexarelin 治疗显着增加了脉动性 GH 分泌，而 MC4RKO 小鼠的基础 GH 分泌没有可检测到的改变。接受治疗的小鼠脂肪组织中的脂肪分解和脂质氧化增加，肝脏中脂肪从头生成减少，导致内脏脂肪量减少，肝脏中甘油三酯含量降低，循环游离脂肪酸水平保持不变。重要的是，海瑞林治疗改善了全身胰岛素敏感性，但没有改变葡萄糖耐量、胰岛素水平或胰岛素样生长因子 1 (IGF-1) 水平。hexarelin 的代谢作用可能是通过 GH 的直接作用实现的，如内脏脂肪组织和肝脏中参与 GH 信号通路的基因表达水平增加所表明的那样。综上所述，hexarelin 治疗刺激了 GH 的搏动分泌，并减少了肥胖 MC4RKO 小鼠内脏库和肝脏中的脂肪积累，改善了胰岛素敏感性，而没有改变胰岛素或 IGF-1 的水平。它通过激活垂体中的 GHSR 来增强脉动性 GH 分泌，为控制肥胖提供了证据。