Relationship between Innate Immune Response Toll-Like Receptor 4 (TLR-4) and the Pathophysiological Process of Obesity Cardiomyopathy

Abstract Background Obesity is a chronic low-grade inflammation condition related to cardiac disorders. However, the mechanism responsible for obesity-related cardiac inflammation is unclear. The toll-like receptor 4 (TLR-4) belongs to a receptor of the transmembrane family responsible for the immune response whose activation stimulates the production of proinflammatory cytokines. Objective To test whether the activation of the TLR-4 receptor participates in the obesity cardiomyopathy process, due to cytokine production through NF-ĸB activation. Methods Male Wistar rats were randomized into two groups: the control group (C, n= 8 animals) that received standard diet/water and the obese group (OB, n= 8 animals) that were fed a high sugar-fat diet and water plus 25% of sucrose for 30 weeks. Nutritional analysis: body weight, adiposity index, food, water, and caloric intake. Obesity-related disorders analysis: plasma glucose, uric acid and triglycerides, HOMA-IR, systolic blood pressure, TNF-α in adipose tissue. Cardiac analysis included: TLR-4 and NF-ĸB protein expression, TNF-α and IL-6 levels. Comparison by unpaired Student’s t-test or Mann- Whitney test with a p-value < 0.05 as statistically significant. Results The OB group showed obesity, high glucose, triglycerides, uric acid, HOMA, systolic blood pressure, and TNF-α in adipose tissue. OB group presented cardiac remodeling and diastolic dysfunction. TLR-4 and NF-ĸB expression and cytokine levels were higher in OB. Conclusion Our findings conclude that, in an obesogenic condition, the inflammation derived from cardiac TLR-4 activation can be a mechanism able to lead to remodeling and cardiac dysfunction.

**摘要**
**背景** 肥胖是一种与心脏疾病相关的慢性低度炎症状态，但其介导肥胖相关心脏炎症的具体机制尚未阐明。Toll样受体4（toll-like receptor 4, TLR-4）属于参与免疫应答的跨膜受体家族成员，其活化可诱导促炎细胞因子的产生。
**目的** 本研究旨在探讨TLR-4受体的活化是否通过核因子κB（nuclear factor kappa-B, NF-κB）通路介导细胞因子产生，参与肥胖性心肌病的发生进程。
**方法** 将雄性Wistar大鼠随机分为两组：对照组（C组，n=8）给予标准饲料与饮用水，肥胖组（OB组，n=8）给予高糖高脂饲料与饮用水，并辅以25%蔗糖饮水，造模周期为30周。检测指标包括：①营养状态分析：体质量、肥胖指数、食物摄入量、饮水量及热量摄入；②肥胖相关指标分析：血浆葡萄糖、尿酸、甘油三酯水平，胰岛素抵抗指数（HOMA-IR）、收缩压，以及脂肪组织肿瘤坏死因子-α（TNF-α）水平；③心脏相关指标分析：TLR-4与NF-κB蛋白表达量，以及TNF-α与白细胞介素-6（IL-6）水平。统计学分析采用非配对Student t检验或曼-惠特尼U检验，以P<0.05为差异具有统计学意义。
**结果** 与对照组相比，OB组大鼠呈现肥胖表型，血浆葡萄糖、甘油三酯、尿酸水平升高，HOMA-IR指数、收缩压及脂肪组织TNF-α水平均显著上调；OB组同时出现心脏重构与舒张功能障碍；OB组心脏组织中TLR-4与NF-κB的表达量以及细胞因子水平均显著升高。
**结论** 本研究结果表明，在肥胖诱导的病理状态下，心脏TLR-4活化介导的炎症反应可能是引发心脏重构与心功能障碍的潜在机制。