ER stress aggravates diaphragm weakness through activating PERK/JNK signaling in obesity hypoventilation syndrome

Abstract

Objective: 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.Methods: 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.Results: 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) Xiaoxin Xiang, Yanhua Zhu, and Xuya Pan contributed equally to this study.Xiaoyue Zhang, Yanming Chen, and Guojun Shi are also equal contributors.

Symptoms Arising From the Diaphragm Muscle: Function and Dysfunction

“…People with obesity may suffer from obesity hypoventilation syndrome (OHS), a diaphragmatic weakness due to structural alterations such as excess accumulation of lipids with lipotoxic effects on contractile cells and reduction of lung volumes due to non-physiological positioning of the diaphragm caused by abdominal fat mass [ 16 , 17 ]. Chronic kidney disease (CKD) patients, with or without hemodialysis, demonstrate a reduction in diaphragm strength and thickness, whose alterations cause dyspnea, hiccups, and generalized fatigue [ 18 ].…”

The hedonic overdrive model best explains high‐fat diet‐induced obesity in C57BL/6 mice

“…This is called the passive overconsumption model [19][20][21][22]. By this model, the animals overconsume calories, driving them into positive energy balance and weight gain, but they do so because the primary mechanism by which food intake is regulated is by its weight [19,21,[23][24][25]. Because high-fat foods have a greater energy density [26], if an animal simply continued to eat the same weight of food after being swapped from a low-fat to a high-fat diet, then it would get fat by passively overconsuming calories.…”