Ciriello John, Moreau Jason M, Caverson Monica M, Moranis Rebecca
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
Front Physiol. 2022 Jan 27;12:767318. doi: 10.3389/fphys.2021.767318. eCollection 2021.
Chronic intermittent hypoxia (CIH), a pathophysiological manifestation of obstructive sleep apnea (OSA), is strongly correlated with obesity, as patients with the disease experience weight gain while exhibiting elevated plasma levels of leptin. This study was done to determine whether a relationship may exist between CIH and obesity, and body energy balance and leptin signaling during CIH. Sprague-Dawley rats were exposed to 96 days of CIH or normoxic control conditions, and were assessed for measures of body weight, food and water intake, and food conversion efficiency. At the completion of the study leptin sensitivity, locomotor activity, fat pad mass and plasma leptin levels were determined within each group. Additionally, the hypothalamic arcuate nucleus (ARC) was isolated and assessed for changes in the expression of proteins associated with leptin receptor signaling. CIH animals were found to have reduced locomotor activity and food conversion efficiency. Additionally, the CIH group had increased food and water intake over the study period and had a higher body weight compared to normoxic controls at the end of the study. Basal plasma concentrations of leptin were significantly elevated in CIH exposed animals. To test whether a resistance to leptin may have occurred in the CIH animals due to the elevated plasma levels of leptin, an acute exogenous (ip) leptin (0.04 mg/kg carrier-free recombinant rat leptin) injection was administered to the normoxic and CIH exposed animals. Leptin injections into the normoxic controls reduced their food intake, whereas CIH animals did not alter their food intake compared to vehicle injected CIH animals. Within ARC, CIH animals had reduced protein expression of the short form of the obese (leptin) receptor (isoform OBR) and showed a trend toward an elevated protein expression of the long form of obese (leptin) receptor (OBRb). In addition, pro-opiomelanocortin (POMC) protein expression was reduced, but increased expression of the phosphorylated extracellular-signal-regulated kinase 1/2 (pERK1/2) and of the suppressor of cytokine signaling 3 (SOCS3) proteins was observed in the CIH group, with little change in phosphorylated signal transducer and activator of transcription 3 (pSTAT3). Taken together, these data suggest that long-term exposure to CIH, as seen in obstructive sleep apnea, may contribute to a state of leptin resistance promoting an increase in body weight.
慢性间歇性缺氧（CIH）是阻塞性睡眠呼吸暂停（OSA）的一种病理生理表现，与肥胖密切相关，因为患有该疾病的患者体重增加，同时血浆瘦素水平升高。本研究旨在确定CIH与肥胖之间是否可能存在关系，以及CIH期间的身体能量平衡和瘦素信号传导情况。将Sprague-Dawley大鼠暴露于96天的CIH或常氧对照条件下，并评估其体重、食物和水摄入量以及食物转化效率。在研究结束时，测定每组大鼠的瘦素敏感性、运动活动、脂肪垫质量和血浆瘦素水平。此外，分离下丘脑弓状核（ARC）并评估与瘦素受体信号传导相关蛋白质表达的变化。发现CIH组动物的运动活动和食物转化效率降低。此外，在研究期间，CIH组的食物和水摄入量增加，并且在研究结束时，与常氧对照组相比，体重更高。暴露于CIH的动物的基础血浆瘦素浓度显著升高。为了测试由于血浆瘦素水平升高，CIH组动物是否可能出现对瘦素的抵抗，向常氧和CIH暴露的动物腹腔注射急性外源性（腹腔注射）瘦素（0.04 mg/kg无载体重组大鼠瘦素）。向常氧对照组注射瘦素可减少其食物摄入量，而与注射载体的CIH组动物相比，CIH组动物的食物摄入量没有改变。在ARC内，CIH组动物的肥胖（瘦素）受体短型（异构体OBR）的蛋白质表达减少，而肥胖（瘦素）受体长型（OBRb）的蛋白质表达有升高趋势。此外，促阿片黑素皮质素原（POMC）的蛋白质表达减少，但在CIH组中观察到磷酸化细胞外信号调节激酶1/2（pERK1/2）和细胞因子信号传导抑制因子3（SOCS3）蛋白质的表达增加，而磷酸化信号转导和转录激活因子3（pSTAT3）变化不大。综上所述，这些数据表明，阻塞性睡眠呼吸暂停中所见的长期暴露于CIH可能导致瘦素抵抗状态，促进体重增加。
