The Unity of Redox and Structural Remodeling of Brown Adipose Tissue in Hypothyroidism

Brown adipose tissue (BAT) is important for maintaining whole-body metabolic and energy homeostasis. However, the effects of hypothyroidism, one of the most common diseases worldwide, which increases the risk of several metabolic disorders, on BAT redox and metabolic homeostasis remain mostly unknown. We aimed to investigate the dynamics of protein expression, enzyme activity, and localization of antioxidant defense (AD) enzymes in rat interscapular BAT upon induction of hypothyroidism by antithyroid drug methimazole for 7, 15, and 21 days. Our results showed an increased protein expression of CuZn- and Mn-superoxide dismutase, catalase, glutamyl-cysteine ligase, thioredoxin, total glutathione content, and activity of catalase and thioredoxin reductase in hypothyroid rats, compared to euthyroid control. Concomitant with the increase in AD, newly established nuclear, mitochondrial, and peroxisomal localization of AD enzymes was found. Hypothyroidism also potentiated associations between mitochondria, peroxisomes, and lipid bodies, creating specific structural-functional units. Moreover, hypothyroidism induced protein expression and nuclear translocation of a master regulator of redox-metabolic homeostasis, nuclear factor erythroid 2-related factor 2 (Nrf2), and an increased amount of 4-hydroxynonenal (4-HNE) protein adducts. The results indicate that spatiotemporal overlap in the remodeling of AD is orchestrated by Nrf2, implicating the role of 4-HNE in this process and suggesting the potential mechanism of redox-structural remodeling during BAT adaptation in hypothyroidism.