Zhang Xin, Wang Lu, Wang Yubo, He Linjuan, Xu Doudou, Yan Enfa, Guo Jianxin, Ma Chenghong, Zhang Pengguang, Yin Jingdong
State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 100193, Beijing, China.
Molecular Design Breeding Frontier Science Center of the Ministry of Education, 100193, Beijing, China.
Cell Death Discov. 2023 Mar 9;9(1):87. doi: 10.1038/s41420-023-01389-y.
The normal function of skeletal muscle and adipose tissue ensures whole-body glucose homeostasis. Ca release channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) plays a vital role in regulating diet-induced obesity and disorders, but its functions in peripheral tissue regulating glucose homeostasis remain unexplored. In this study, mice with Ip3r1 specific knockout in skeletal muscle or adipocytes were used for investigating the mediatory role of IP3R1 on whole-body glucose homeostasis under normal or high-fat diet. We reported that IP3R1 expression levels were increased in the white adipose tissue and skeletal muscle of diet-induced obese mice. Ip3r1 knockout in skeletal muscle improved glucose tolerance and insulin sensitivity of mice on a normal chow diet, but worsened insulin resistance in diet-induced obese mice. These changes were associated with the reduced muscle weight and compromised Akt signaling activation. Importantly, Ip3r1 deletion in adipocytes protected mice from diet-induced obesity and glucose intolerance, mainly due to the enhanced lipolysis and AMPK signaling pathway in the visceral fat. In conclusion, our study demonstrates that IP3R1 in skeletal muscle and adipocytes exerts divergent effects on systemic glucose homeostasis, and characterizes adipocyte IP3R1 as a promising target for treating obesity and type 2 diabetes.
骨骼肌和脂肪组织的正常功能确保了全身葡萄糖稳态。钙释放通道肌醇1,4,5-三磷酸受体1（IP3R1）在调节饮食诱导的肥胖和紊乱中起着至关重要的作用，但其在调节外周组织葡萄糖稳态中的功能仍未得到探索。在本研究中，利用骨骼肌或脂肪细胞中Ip3r1特异性敲除的小鼠，研究IP3R1在正常或高脂饮食下对全身葡萄糖稳态的介导作用。我们报道，饮食诱导的肥胖小鼠的白色脂肪组织和骨骼肌中IP3R1表达水平升高。骨骼肌中Ip3r1敲除改善了正常饮食小鼠的葡萄糖耐量和胰岛素敏感性，但恶化了饮食诱导的肥胖小鼠的胰岛素抵抗。这些变化与肌肉重量减轻和Akt信号激活受损有关。重要的是，脂肪细胞中Ip3r1缺失可保护小鼠免受饮食诱导的肥胖和葡萄糖不耐受，主要是由于内脏脂肪中脂解作用增强和AMPK信号通路激活。总之，我们的研究表明，骨骼肌和脂肪细胞中的IP3R1对全身葡萄糖稳态发挥不同的作用，并将脂肪细胞IP3R1确定为治疗肥胖和2型糖尿病的一个有前景的靶点。
