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Theranostics 2022; 12(3):1187-1203. doi:10.7150/thno.63067 This issue Cite

Research Paper

Antibiotic Azithromycin inhibits brown/beige fat functionality and promotes obesity in human and rodents

Jian Yu^1*, Xin Chen^1*, Yuanjin Zhang^1*, Xiangdi Cui¹, Zhe Zhang¹, Wenxiu Guo¹, Dongmei Wang¹, Shengbo Huang¹, Yanru Chen², Yepeng Hu³, Cheng Zhao¹, Jin Qiu¹, Yu Li¹, Meiyao Meng¹, Mingwei Guo¹, Fei Shen⁴, Mengdi Zhang⁵, Ben Zhou⁵, Xuejiang Gu³, Jiqiu Wang², Xin Wang^1✉, Xinran Ma^1✉, Lingyan Xu^1✉

1. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
2. Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
3. Department of Endocrine and Metabolic Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
4. Key Laboratory of Adolescent Health Assessment and Exercise Intervention, Ministry of Education, East China Normal University, Shanghai, China.
5. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Dr. Xin Wang, xwangecnu.edu.cn; Dr. Xinran Ma, xrmaecnu.edu.cn; Dr. Lingyan Xu, lyxuecnu.edu.cn

Abstract

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.

Methods: 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.

Results: 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.

Conclusions: Taken together, this work highlights the possible role of azithromycin in obesity epidemic and presents strategies for safe applications of antibiotics in the future.

Keywords: Obesity, Azithromycin, Adipose tissue, Energy metabolism, Oxidative damage

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