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Iron chelation increases beige fat differentiation and metabolic activity, preventing and treating obesity.

ABSTRACT: Beige and brown fat consume glucose and lipids to produce heat, using uncoupling protein 1 (UCP1). It is thought that full activation of brown adipose tissue (BAT) may increase total daily energy expenditure by 20%. Humans normally have more beige and potentially beige-able fat than brown fat. Strategies to increase beige fat differentiation and activation may be useful for the treatment of obesity and diabetes. Mice were fed chow or high-fat diet (HFD) with or without the iron chelator deferasirox. Animals fed HFD + deferasirox were markedly lighter than their HFD controls with increased energy expenditure (12% increase over 24 h, p < 0.001). Inguinal fat from HFD + deferasirox mice showed increased beige fat quantity with greater Ucp1 and Prdm16 expression. Inguinal adipose tissue explants were studied in a Seahorse bioanalyser and energy expenditure was significantly increased. Deferasirox was also effective in established obesity and in ob/ob mice, indicating that intact leptin signalling is not needed for efficacy. These studies identify iron chelation as a strategy to preferentially activate beige fat. Whether activating brown/beige fat is effective in humans is unproven. However, depleting iron to low-normal levels is a potential therapeutic strategy to improve obesity and related metabolic disorders, and human studies may be warranted.

SUBMITTER: Nazari M

PROVIDER: S-EPMC8760280 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Iron chelation increases beige fat differentiation and metabolic activity, preventing and treating obesity.

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