Introduction: Brown Adipose Tissue (BAT) dysfunction is closely linked to obesity and metabolic diseases. Thyroid hormones (THs) and their analogues profoundly influence BAT thermogenesis. Besides their crucial role in brown adipocyte recruitment, THs also target mitochondria. Maintaining mitochondrial homeostasis involves various mechanisms, collectively referred to as mitochondrial quality control (MQC), including the unfolded protein response (UPRmt), mitochondrial fission, fusion, mitophagy, biogenesis, and DNA repair. Pathophysiological conditions like obesity induce excessive nutrient oxidation, leading to mitochondrial stress and compromising integrity and functionality. This study analyses and compares the effect of T2 and T3 administration on mitochondrial homeostasis in mice with obesity. Methods: Obesity was induced over 15 weeks through a high-fat diet. Cytochrome C Oxidase (COX) activity was determined polarographically. The serum levels of 8-OHdG were determined by a DNA/RNA Oxidative Damage ELISA kit. BAT Mitochondrial H2O2 content was assessed by Hydrogen Peroxide Assay Kit. Key players in mitochondrial Quality Control processes were measured using RT-qPCR and western blotting. Results: In our experimental model both T2 and T3 mitigate mitochondrial dysfunction in BAT. The two iodothyronines reduce adiposity, increase BAT mass and Specific COX activity, indicating an enhanced termogenic effect. Furthermore, T2 and T3 counteract oxidative stress at the systemic and tissue levels, activate UPRmt, enhance antioxidant machinery, and improve diet-induced alterations in all MQC processes. Conclusion: In conclusion, these findings support the notion that T2 and T3 mitigate BAT mitochondrial dysfunctions in mice with obesity. However, it is important to emphasize that T2, at the concentrations we used, does not exhibit thyrotoxic effects. Given the ongoing obesity epidemic, identifying a potential therapeutic agent preserving BAT mitochondria functionality and adaptive thermogenesis could represent a promising strategy to counteract weight gain and metabolic diseases.
3,5-Diiodothyronine (T2) and 3,3’,5-Triiodothyronine (T3) mitigate Brown Adipose Tissue Mitochondrial Dysfunction in mice with obesity: Implications for Therapeutic Strategies in Metabolic Diseases
Giuseppe Petito;Arianna Cuomo;Maria Ventriglia;Antonia Lanni;Rosalba Senese
2024
Abstract
Introduction: Brown Adipose Tissue (BAT) dysfunction is closely linked to obesity and metabolic diseases. Thyroid hormones (THs) and their analogues profoundly influence BAT thermogenesis. Besides their crucial role in brown adipocyte recruitment, THs also target mitochondria. Maintaining mitochondrial homeostasis involves various mechanisms, collectively referred to as mitochondrial quality control (MQC), including the unfolded protein response (UPRmt), mitochondrial fission, fusion, mitophagy, biogenesis, and DNA repair. Pathophysiological conditions like obesity induce excessive nutrient oxidation, leading to mitochondrial stress and compromising integrity and functionality. This study analyses and compares the effect of T2 and T3 administration on mitochondrial homeostasis in mice with obesity. Methods: Obesity was induced over 15 weeks through a high-fat diet. Cytochrome C Oxidase (COX) activity was determined polarographically. The serum levels of 8-OHdG were determined by a DNA/RNA Oxidative Damage ELISA kit. BAT Mitochondrial H2O2 content was assessed by Hydrogen Peroxide Assay Kit. Key players in mitochondrial Quality Control processes were measured using RT-qPCR and western blotting. Results: In our experimental model both T2 and T3 mitigate mitochondrial dysfunction in BAT. The two iodothyronines reduce adiposity, increase BAT mass and Specific COX activity, indicating an enhanced termogenic effect. Furthermore, T2 and T3 counteract oxidative stress at the systemic and tissue levels, activate UPRmt, enhance antioxidant machinery, and improve diet-induced alterations in all MQC processes. Conclusion: In conclusion, these findings support the notion that T2 and T3 mitigate BAT mitochondrial dysfunctions in mice with obesity. However, it is important to emphasize that T2, at the concentrations we used, does not exhibit thyrotoxic effects. Given the ongoing obesity epidemic, identifying a potential therapeutic agent preserving BAT mitochondria functionality and adaptive thermogenesis could represent a promising strategy to counteract weight gain and metabolic diseases.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
