Skeletal Muscle Growth Hormone Receptor Signaling Regulates Basal, but Not Fasting-Induced, Lipid Oxidation

BackgroundGrowth hormone (GH) stimulates whole-body lipid oxidation, but its regulation of muscle lipid oxidation is not clearly defined. Mice with a skeletal muscle-specific knockout of the GH receptor (mGHRKO model) are protected from high fat diet (HFD)–induced insulin resistance and display increased whole-body carbohydrate utilization. In this study we used the mGRHKO mice to investigate the role of muscle GHR signaling on lipid oxidation under regular chow (RC)- and HFD- fed conditions, and in response to fasting. Methodology/Principal FindingsExpression of lipid oxidation genes was analyzed by real-time PCR in the muscles of RC- and HFD- fed mice, and after 24 h fasting in the HFD-fed mice. Expression of lipid oxidation genes was lower in the muscles of the mGHRKO mice relative to the controls, irrespective of diet. However, in response to 24 h fasting, the HFD-fed mGHRKO mice displayed up-regulation of lipid oxidation genes similar to the fasted controls. When subjected to treadmill running challenge, the HFD-fed mGHRKO mice demonstrated increased whole-body lipid utilization. Additionally, under fasted conditions, the adipose tissue of the mGHRKO mice displayed increased lipolysis as compared to both the fed mGHRKO as well as the fasted control mice. Conclusions/SignificanceOur data show that muscle GHR signaling regulates basal lipid oxidation, but not the induction of lipid oxidation in response to fasting. We further demonstrate that muscle GHR signaling is involved in muscle-adipose tissue cross-talk; however the mechanisms mediating this remain to be elucidated.背景：生长激素（growth hormone, GH）可刺激全身脂质氧化，但其对肌肉脂质氧化的调控机制尚未明确。骨骼肌特异性敲除生长激素受体的小鼠（mGHRKO模型）可免受高脂饮食（high fat diet, HFD）诱导的胰岛素抵抗，且全身碳水化合物利用能力提升。本研究利用该mGHRKO小鼠模型，探究普通饲料（regular chow, RC）与高脂饮食喂养条件下，以及禁食状态中，肌肉GHR信号通路对脂质氧化的调控作用。 方法与主要结果：本研究通过实时荧光定量PCR（real-time PCR），分析了普通饲料及高脂饮食喂养的小鼠，以及高脂饮食喂养且禁食24小时后的小鼠肌肉组织中脂质氧化相关基因的表达水平。结果显示，无论饮食类型如何，mGHRKO小鼠的肌肉组织内脂质氧化相关基因的表达量均低于对照组小鼠。但在禁食24小时后，高脂饮食喂养的mGHRKO小鼠的脂质氧化相关基因表达出现上调，其上调幅度与禁食对照组小鼠相当。在接受跑台运动负荷实验时，高脂饮食喂养的mGHRKO小鼠展现出更强的全身脂质利用能力。此外，在禁食状态下，相较于普通喂养的mGHRKO小鼠与禁食对照组小鼠，mGHRKO小鼠的脂肪组织脂解作用显著增强。 结论与意义：本研究数据表明，肌肉GHR信号通路可调控基础状态下的脂质氧化，但不参与禁食诱导的脂质氧化过程。我们进一步证实，肌肉GHR信号通路参与肌肉-脂肪组织的交叉对话，但其具体介导机制仍有待阐明。