Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Theranostics. 2022 Jan 1;12(3):1187-1203. doi: 10.7150/thno.63067. eCollection 2022.
Obesity, a metabolic disease caused by multiple factors, has become a global health problem. In addition to nutrient intake and sedentary lifestyle, environmental pollutants exposure has been shown to be involved in obesity epidemics. Antibiotics, a new type of environmental pollutant, have been widely used in animal husbandry, aquaculture and microorganism. However, the effects of antibiotics exposure on fat metabolism and metabolic diseases are largely unknown. We screened major types of antibiotics to examine their effects on the differentiation capacity and thermogenic functionality of brown and beige adipocytes, and found that azithromycin, one major kind of macrolide antibiotics suppressed brown and beige adipocyte functionality. We thus examined azithromycin accretion in adipose tissues of obese patients that correlates with BMI by high performance liquid chromatography-tandem mass spectrometry and systematically explore the influences of azithromycin on adiposity and metabolic performance in mice under high diet. Azithromycin (macrolides) inhibits the mitochondrial and thermogenic gene programs of brown and beige adipocytes, thus disrupting their mitochondrial function and thermogenic response. Consistently, azithromycin treatment are more prone to diet-induced obesity in mice, and this was associated with impaired energy expenditure. Importantly, azithromycin is more accumulated in adipose tissue of obese patients and correlates with BMI and body weight. Mechanistically, we found that azithromycin inhibits mitochondria respiratory complex I protein levels and increases reactive oxidative species (ROS) levels, which causes damage of mitochondrial function in brown and beige adipocytes. The deleterious effects of azithromycin can be ameliorated by antioxidant N-acetyl-L-cysteine. Taken together, this work highlights the possible role of azithromycin in obesity epidemic and presents strategies for safe applications of antibiotics in the future.
肥胖是一种由多种因素引起的代谢性疾病，已成为全球性的健康问题。除了营养摄入和久坐的生活方式外，环境污染物暴露也被认为与肥胖流行有关。抗生素作为一种新型环境污染物，已广泛应用于畜牧业、水产养殖业和微生物领域。然而，抗生素暴露对脂肪代谢和代谢性疾病的影响在很大程度上尚未可知。我们筛选了主要类型的抗生素，以研究它们对棕色和米色脂肪细胞分化能力和产热功能的影响，发现大环内酯类抗生素之一的阿奇霉素抑制了棕色和米色脂肪细胞的功能。因此，我们通过高效液相色谱-串联质谱法检测了肥胖患者脂肪组织中与 BMI 相关的阿奇霉素蓄积情况，并系统地研究了阿奇霉素在高脂肪饮食诱导的肥胖小鼠中对脂肪堆积和代谢性能的影响。阿奇霉素（大环内酯类）抑制棕色和米色脂肪细胞的线粒体和产热基因程序，从而破坏其线粒体功能和产热反应。一致地，阿奇霉素处理更容易导致肥胖小鼠的饮食诱导肥胖，这与能量消耗受损有关。重要的是，阿奇霉素在肥胖患者的脂肪组织中积累更多，与 BMI 和体重相关。从机制上讲，我们发现阿奇霉素抑制线粒体呼吸复合物 I 蛋白水平并增加活性氧（ROS）水平，从而导致棕色和米色脂肪细胞中线粒体功能受损。抗氧化剂 N-乙酰-L-半胱氨酸可减轻阿奇霉素的有害作用。总之，这项工作强调了阿奇霉素在肥胖流行中的可能作用，并提出了未来安全应用抗生素的策略。
