School of Biomedical Sciences, University of Queensland, St Lucia, QLD, Australia.
Department of Medicine, Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, MN, USA.
FASEB J. 2021 Jan;35(1):e21269. doi: 10.1096/fj.202001924RR.
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.
肥胖个体通常表现出生长激素 (GH) 分泌低下，导致脂质动员减少和脂肪进一步堆积。通过 GH 注射或 GH 释放激素受体激动剂增加肥胖个体 GH 水平的药物方法显示出在减少脂肪方面的有前景的效果。然而，对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 GH 分泌素受体 (GHSR) 激动剂 hexarelin 是否通过刺激内源性 GH 分泌来改善食欲亢进肥胖小鼠模型的代谢。雄性黑素皮质素 4 受体敲除小鼠 (MC4RKO) 进行配对喂养，并通过渗透泵持续输注 hexarelin（10.56μg/天）或载体 3-4 周。Hexarelin 治疗显著增加了 GH 的脉冲式分泌，而基础 GH 分泌没有可检测的改变。治疗后的小鼠表现出脂肪组织中脂解和脂质氧化增加，肝脏中新生脂肪生成减少，导致内脏脂肪质量减少，肝脏中甘油三酯含量减少，循环游离脂肪酸水平不变。重要的是，hexarelin 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，这表明内脏脂肪组织和肝脏中涉及 GH 信号通路的基因表达水平增加。总之，hexarelin 治疗刺激了脉冲式 GH 分泌，减少了肥胖 MC4RKO 小鼠内脏脂肪和肝脏中的脂肪堆积，改善了胰岛素敏感性，而没有改变胰岛素或 IGF-1 水平。它通过激活垂体中的 GHSR 来增强脉冲式 GH 分泌，为肥胖症的治疗提供了证据。
