Zhang Meng, Yang Peilang, Yu Tianyi, Harmsen Martin C, Gao Min, Liu Dan, Shi Yan, Liu Yan, Zhang Xiong
Department of Burn, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, China.
University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Hanzeplein 1 (EA11), 9713GZ Groningen, the Netherlands.
Heliyon. 2022 Mar 17;8(3):e09128. doi: 10.1016/j.heliyon.2022.e09128. eCollection 2022 Mar.
Browning of white adipose tissue is associated with elevated resting metabolic rates and is considered to be one of the indispensable causes of hypermetabolism in burn patients. Hypermetabolism means increased resting energy expenditure, raised body temperature and acute-phase proteins. Persistently elevated levels of circulating stress hormones have been reported to induce browning of subcutaneous white adipose tissue. The lytic cocktail is a combination of medicines pethidine, chlorpromazine, and promethazine that has been used clinically in sedation for the management of patients. As reported this sedative treatment can reduce the expression of catecholamines in major burn rats. Thus, in this paper we focused on the effects of lytic cocktail in the regulation of white adipose tissue browning and hypermetabolism and we further investigated the underlying mechanism.
A 30% total body surface area (TBSA) Ⅲ degree scald rat model was used for this study. The rats were randomly divided into a sham scald group, a scalding with immediate resuscitation group, and a group of scalding with immediate resuscitation and lytic cocktail treatment. The levels of norepinephrine and epinephrine in plasma were dynamically detected. Changes of the rat body weight and food intake were recorded and compared as indexes of metabolism responses after post-scalding. For the study of white adipose tissue browning, inguinal adipose tissue was used. Metabolic changes, while indicatives of white fat browning were measured by PET/CT. The expression of white adipose browning related proteins and the changes of mitochondria number were used to assess browning of inguinal adipose.
The level of plasma catecholamines norepinephrine and epinephrine in the lytic cocktail-treated group was significantly lower than the other two groups. Morphology and PET/CT showed that the inguinal white adipose browning was inhibited in the lytic cocktail treated group, whereas scalding with immediate resuscitation group showed browning of white adipose. The number of mitochondria, the expressions of white adipose browning related proteins in the lytic cocktail group were also significantly lower than that of the group of scalding with immediate resuscitation.
By reducing expression of heat-related proteins, the application of lytic cocktail medicines inhibits the white adipose tissue browning, which suppresses hypermetabolism in scalded rats. The mechanism might be related to decreased expression levels of stress hormones induced by lytic cocktail. This research suggests that lytic cocktails may be an effective treatment for hypermetabolism after severe burn injury.
白色脂肪组织的褐色化与静息代谢率升高有关，被认为是烧伤患者高代谢不可或缺的原因之一。高代谢意味着静息能量消耗增加、体温升高和急性期蛋白增加。据报道，循环应激激素水平持续升高会诱导皮下白色脂肪组织褐色化。溶细胞合剂是哌替啶、氯丙嗪和异丙嗪的药物组合，已在临床上用于患者镇静治疗。据报道，这种镇静治疗可降低重度烧伤大鼠体内儿茶酚胺的表达。因此，在本文中，我们重点研究了溶细胞合剂对白色脂肪组织褐色化和高代谢的调节作用，并进一步探讨了其潜在机制。
本研究采用30%总体表面积（TBSA）Ⅲ度烫伤大鼠模型。将大鼠随机分为假烫伤组、立即复苏烫伤组和立即复苏并接受溶细胞合剂治疗的烫伤组。动态检测血浆中去甲肾上腺素和肾上腺素水平。记录并比较大鼠体重和食物摄入量的变化，作为烫伤后代谢反应的指标。为研究白色脂肪组织褐色化，使用腹股沟脂肪组织。通过PET/CT测量代谢变化，作为白色脂肪褐色化的指标。用白色脂肪褐色化相关蛋白的表达和线粒体数量的变化来评估腹股沟脂肪的褐色化。
溶细胞合剂治疗组血浆儿茶酚胺去甲肾上腺素和肾上腺素水平显著低于其他两组。形态学和PET/CT显示，溶细胞合剂治疗组腹股沟白色脂肪褐色化受到抑制，而立即复苏烫伤组白色脂肪出现褐色化。溶细胞合剂组线粒体数量、白色脂肪褐色化相关蛋白的表达也显著低于立即复苏烫伤组。
通过降低热相关蛋白的表达，溶细胞合剂药物的应用抑制了白色脂肪组织褐色化，从而抑制了烫伤大鼠的高代谢。其机制可能与溶细胞合剂诱导应激激素表达水平降低有关。本研究表明，溶细胞合剂可能是治疗严重烧伤后高代谢的有效方法。
