Department of Endocrinology & Metabolism, Medical Center for Comprehensive Weight Control, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Diabetology & Guangzhou Municipal Key Laboratory of Mechanistic and Translational Obesity Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Obesity (Silver Spring). 2023 Aug;31(8):2076-2089. doi: 10.1002/oby.23809.
Obesity hypoventilation syndrome is associated with diaphragmatic dysfunction. This study aimed to explore the role of endoplasmic reticulum (ER) stress in mediating obesity-induced diaphragmatic dysfunction.
A pulmonary function test and ultrasound were applied to evaluate diaphragmatic function and magnetic resonance imaging was applied to measure diaphragmatic lipid deposition in human patients. For the mechanistic study, obese mice were introduced to a high-fat diet for 24 weeks, followed by diaphragmatic ultrasound measurement, transcriptomic sequencing, and respective biochemical analysis. Automatic force mapping was applied to measure the mechanical properties of C2C12 myotubes.
People with obesity showed significant diaphragm weakness and lipid accumulation, which was further confirmed in obese mice. Consistently, diaphragms from obese mice showed altered gene expression profile in lipid metabolism and activation of ER stress response, indicated by elevated protein kinase R-like ER kinase (PERK) and c-Jun NH -terminal kinase (JNK) activation. In C2C12 myotubes, inhibition of PERK or JNK signaling abrogated lipotoxicity-induced intracellular lipid deposition and insulin resistance. Inhibition of JNK signaling reversed lipotoxicity-induced impairment of elasticity in C2C12 myotubes.
These data suggest that ectopic lipid deposition impairs the diaphragmatic function of people with obesity. Activation of PERK/JNK signaling is involved in the pathogenesis of lipotoxicity-induced diaphragm weakness in obesity hypoventilation syndrome.
肥胖低通气综合征与膈肌功能障碍有关。本研究旨在探讨内质网（ER）应激在介导肥胖引起的膈肌功能障碍中的作用。
应用肺功能试验和超声评估膈肌功能，应用磁共振成像测量膈肌脂质沉积。为了进行机制研究，将肥胖小鼠引入高脂肪饮食 24 周，然后进行膈肌超声测量、转录组测序和相应的生化分析。应用自动力映射测量 C2C12 肌管的力学性能。
肥胖患者表现出明显的膈肌无力和脂质堆积，这在肥胖小鼠中得到了进一步证实。同样，肥胖小鼠的膈肌表现出脂质代谢和 ER 应激反应激活的基因表达谱改变，表现为蛋白激酶 R 样 ER 激酶（PERK）和 c-Jun NH2-末端激酶（JNK）的激活增加。在 C2C12 肌管中，PERK 或 JNK 信号通路的抑制消除了脂毒性诱导的细胞内脂质沉积和胰岛素抵抗。JNK 信号通路的抑制逆转了脂毒性诱导的 C2C12 肌管弹性的损害。
这些数据表明，异位脂质沉积损害肥胖患者的膈肌功能。PERK/JNK 信号通路的激活参与了肥胖低通气综合征中脂毒性诱导的膈肌无力的发病机制。
