Overnutrition in mice impairs thyroid hormone biosynthesis and utilization, causing hypothyroidism, despite remarkable thyroidal adaptations
Jessica Rampy, Alejandra Paola Torres-Manzo, Kendra Hoffsmith, Matthew A. Loberg, Quanhu Sheng, Federico Salas-Lucia, Antonio C. Bianco, Rafael Arrojo e Drigo, Huiying Wang, Vivian L. Weiss, Nancy Carrasco
Jessica Rampy, Alejandra Paola Torres-Manzo, Kendra Hoffsmith, Matthew A. Loberg, Quanhu Sheng, Federico Salas-Lucia, Antonio C. Bianco, Rafael Arrojo e Drigo, Huiying Wang, Vivian L. Weiss, Nancy Carrasco
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Research Article Cell biology Endocrinology Metabolism

Overnutrition in mice impairs thyroid hormone biosynthesis and utilization, causing hypothyroidism, despite remarkable thyroidal adaptations

Abstract

Thyroid hormones (THs [T3 and T4] ) are key regulators of metabolic rate and nutrient metabolism. They are controlled centrally and peripherally in a coordinated manner to elegantly match T3-mediated energy expenditure (EE) with energy availability. Hypothyroidism reduces EE and has long been blamed for obesity; however, emerging evidence suggests that, instead, obesity may drive thyroid dysfunction. Thus, we used a mouse model of diet-induced obesity to determine its direct effects on thyroid histopathology and function, deiodinase activity, and T3 action. Strikingly, overnutrition induced hypothyroidism within 3 weeks. Levels of thyroidal THs and their precursor protein thyroglobulin decreased, and ER stress was induced, indicating that thyroid function was directly impaired. We also observed pronounced histological and vascular expansion in the thyroid. Overnutrition additionally suppressed T4 activation, rendering the mice resistant to T4 and reducing EE. Our findings collectively show that overnutrition deals a double strike to TH biosynthesis and action, despite large efforts to adapt — but, fortunately, thyroid dysfunction in mice can be reversed by weight loss. In humans, BMI correlated with thyroidal vascularization, importantly demonstrating preliminary translatability. These studies lay the groundwork for obesity therapies that tackle hypothyroidism, which are much needed, as no current obesity treatment works for everyone.

Authors

Jessica Rampy, Alejandra Paola Torres-Manzo, Kendra Hoffsmith, Matthew A. Loberg, Quanhu Sheng, Federico Salas-Lucia, Antonio C. Bianco, Rafael Arrojo e Drigo, Huiying Wang, Vivian L. Weiss, Nancy Carrasco

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Figure 7

Thyroid dysfunction caused by overnutrition is reversible.

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Thyroid dysfunction caused by overnutrition is reversible. Male mice wer...
Male mice were placed on the HF+SD for 6 weeks and then switched to the CD for 6 weeks (REV). BW was measured weekly (A). BAT, iWAT, and gWAT depots were weighed immediately after dissection (B). Terminal sera were analyzed by immunoassay for total T3 (C). Plasma and sera were analyzed by immunoassay for total T4 (D) and TSH (E). Some thyroids were weighed immediately upon dissection (F). Other thyroids were fully proteolyzed, and liberated T4 (G) and T3 (H) were then measured by immunoassay and normalized to the thyroidal protein. Other thyroids were fixed for H&E staining, and H&E images were then blindly scored for extent of interfollicular vascular/lymphatic space (I). Western blot of thyroid homogenate was performed for TG and quantitated (J). Data are representative of 2 separate cohorts of mice. These cohorts consisted of n = 15/group (A), n = 7/group (B). Data are results from 2 separate cohorts of mice per timepoint: combined CD n = 10, REV n = 15 (G and H). n = 15/group (D and E). Dotted line represents switch from HF+SD to CD for REV mice. Data were analyzed by 2-way ANOVA with repeated measures (A, D, and E), unpaired Student’s t test with Welch’s correction (B, C, F–H, and J), or Mann-Whitney test (I). *P < 0.05, **P < 0.01, & ****P < 0.0001 versus controls at the same timepoint. #P < 0.05, ##P < 0.01, and ###P < 0.001 versus week 0 within the same diet group.