Chronic Exposure to Environmental Concentrations of Tetrabromobisphenol A Disrupts Insulin and Lipid Homeostasis in Diet-Induced Obese Mice

Tetrabromobisphenol A (TBBPA), a widely used brominated flame retardant in consumer products, has raised significant health concerns. However, the long-term metabolic effects of chronic exposure to environmentally relevant TBBPA concentrations, particularly in the context of modern high-calorie diets, remain poorly understood. Here, we show that C57BL/6J mice fed a high-fat diet and exposed to 20 or 50 nmol/kg/day TBBPA for 120 days exhibited increased body weight, aggravated fat accumulation, impaired glucose tolerance, insulin resistance, and dyslipidemia. Mechanistic investigations revealed that TBBPA exposure led to decreased norepinephrine levels, consequently reducing energy expenditure. It disrupts hepatic insulin signaling and upregulates G6Pase, thereby increasing the level of liver glucose production. Furthermore, TBBPA enhances hepatic cholesterol synthesis by elevating protein levels of HMGCR, which is the rate-limiting enzyme in cholesterol biosynthesis. This effect is mediated through increased expression of USP20, a specific deubiquitinating enzyme for HMGCR. Additionally, TBBPA modestly enhances fatty acid biosynthesis without significantly affecting lipolysis or fatty acid oxidation. Our research reveals novel molecular pathways through which environmental TBBPA exposure disrupts metabolic balance, potentially exacerbating obesity-related health issues. These findings highlight the synergistic effects between environmental pollutants and modern calorie-dense diets on metabolic health, emphasizing the importance of considering multiple factors in obesity-related disorders.