Lovell Andrew J, Hoecht Evan M, Hucik Barbora, Cervone Daniel T, Dyck David J
Department of Human Health and Nutritional Sciences, University of Guelph, Ontario, N1G2W1, Canada.
Metabol Open. 2022 Mar 18;14:100182. doi: 10.1016/j.metop.2022.100182. eCollection 2022 Jun.
Recent findings indicate that ghrelin, particularly the unacylated form (UnAG), acutely stimulates skeletal muscle fatty acid oxidation (FAO) and can preserve insulin signaling and insulin-stimulated glucose uptake in the presence of high concentrations of saturated fatty acids. However, we recently reported that the stimulatory effect of ghrelin on FAO and subsequent ability to protect insulin stimulated glucose uptake was lost following 6-weeks (6w) of chronic high fat feeding. In the current study we examined the effects of both short-term 5 day (5d) and chronic 6w high-fat diet (HFD) on muscle ghrelin response, and whether exercise training could prevent the development of muscle ghrelin resistance with 6w of HFD.
Soleus muscle strips were isolated from male rats to determine the direct effects of acylated (AG) and UnAG isoforms on FAO and glucose uptake. A 5d HFD did not alter the response of soleus muscle to AG or UnAG. Conversely, 6w of HFD was associated with a loss of ghrelin's ability to stimulate FAO and protect insulin stimulated glucose uptake. Muscle response to UnAG remained intact following the 6w HFD with chronic exercise training. Unexpectedly, muscle response to both AG and UnAG was also lost after 6w of low-fat diet (LFD) consumption. Protein content of the classic ghrelin receptor, GHS-R1a, was not affected by diet or training. Corticotropin-releasing hormone receptor-2 (CRF-2R) content, a putative receptor for ghrelin in muscle, was significantly decreased in soleus from 6w HFD-fed animals and increased following exercise training. This may explain the protection of UnAG response with training in HFD-fed rats but does not explain why ghrelin response was also lost in LFD-fed animals.
UnAG protects muscle glucose uptake during acute lipid oversupply, likely due to its ability to stimulate FAO. This effect is lost in 6w HFD-fed animals but protected with exercise training. Unexpectedly, ghrelin response was lost in 6w LFD-fed animals. The loss of ghrelin response in muscle with a LFD cannot be explained by a change in putative ghrelin receptor content. We believe that the sedentary nature of the animals is a major factor in the development of muscle ghrelin resistance and warrants further research.
最近的研究结果表明，胃饥饿素，尤其是去酰基化形式（UnAG），可急性刺激骨骼肌脂肪酸氧化（FAO），并能在高浓度饱和脂肪酸存在的情况下维持胰岛素信号传导以及胰岛素刺激的葡萄糖摄取。然而，我们最近报道，在慢性高脂喂养6周（6w）后，胃饥饿素对脂肪酸氧化的刺激作用以及随后保护胰岛素刺激的葡萄糖摄取的能力丧失。在本研究中，我们研究了短期5天（5d）和慢性6w高脂饮食（HFD）对肌肉胃饥饿素反应的影响，以及运动训练是否可以预防6w高脂饮食导致的肌肉胃饥饿素抵抗的发生。
从雄性大鼠分离比目鱼肌条，以确定酰基化（AG）和去酰基化胃饥饿素亚型对脂肪酸氧化和葡萄糖摄取的直接影响。5d高脂饮食并未改变比目鱼肌对AG或UnAG的反应。相反，6w高脂饮食与胃饥饿素刺激脂肪酸氧化和保护胰岛素刺激的葡萄糖摄取的能力丧失有关。经过慢性运动训练，6w高脂饮食后肌肉对UnAG的反应保持完整。出乎意料的是，在食用6w低脂饮食（LFD）后，肌肉对AG和UnAG的反应也丧失了。经典胃饥饿素受体GHS-R1a的蛋白质含量不受饮食或训练的影响。促肾上腺皮质激素释放激素受体-2（CRF-2R）的含量，一种肌肉中胃饥饿素的假定受体，在6w高脂饮食喂养的动物的比目鱼肌中显著降低，而在运动训练后增加。这可能解释了在高脂饮食喂养的大鼠中训练对UnAG反应的保护作用，但无法解释为什么在低脂饮食喂养的动物中胃饥饿素反应也丧失。
UnAG在急性脂质供应过多期间保护肌肉葡萄糖摄取，可能是由于其刺激脂肪酸氧化的能力。这种作用在6w高脂饮食喂养的动物中丧失，但通过运动训练得到保护。出乎意料的是，在6w低脂饮食喂养的动物中胃饥饿素反应丧失。低脂饮食导致肌肉中胃饥饿素反应丧失不能用假定的胃饥饿素受体含量的变化来解释。我们认为动物的久坐不动性质是肌肉胃饥饿素抵抗发展的一个主要因素，值得进一步研究。
