Endocrine Abstracts

Objective: Energy homeostasis is maintained through a complex interplay of processes, like energy substrate shuttling, breakdown, storage, and distribution. Thyroid hormones (THs) are key modulators of energy metabolism in the liver. In adult mouse liver, local hepatic TH availability is mediated via deiodinases, Dio1 and Dio3. During development, Dio3 is particularly important to provide protection from high concentration of maternal T3 and diminished in adulthood. However, local re-expression of Dio3 is evident upon cancer development, tissue damage and fasting.

Method: To assess the impact of modulating local TH availability on liver energy homeostasis, we used a mouse model with hepatocyte-specific genetic deletion of Dio3 (Alb-Cre; Dio3fl/fl). Evaluation of energy metabolism was carried out via metabolic phenotyping and indirect calorimetry, as well as via analysis of hepatic energy storage, such as hepatic triglyceride and glycogen content.

Result: In the first characterization, three-month-old male and female Alb-Cre; Dio3fl/fl mice fed with normal chow showed regular growth and organ size, circulating TH concentrations (T4, T3, rT3) and hepatic expression of T3-regulated genes. However, normal chow fed female Alb-Cre; Dio3fl/fl mice displayed elevated hepatic triglyceride and glycogen content. On the one hand, fed with a western diet for 12 weeks, female Alb-Cre; Dio3fl/fl mice tended to use more lipid as energy source based on metabolic characterization (e.g., body composition, RER, fatty acid oxidation), accompanied by a lower food and water intake. However, these mice showed similar weight gain as their controls, indicating an altered energy metabolism. On the other hand, during 24 hours fasting, female Alb-Cre; Dio3fl/fl exhibited impaired energy expenditure reduction and therefore a higher loss of lean mass, suggesting dysregulated energy metabolism. However, there was no difference in any of these parameters between male Alb -Cre; Dio3fl/fl mice and their controls.

Conclusion: Based on our data of 12 w dietary intervention and 24 h fasting with TH-related metabolic analysis, hepatic Dio3 plays a role in adaptation of the energy metabolism in a sex-dependent manner.