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

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) to 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 the TH precursor protein thyroglobulin decreased, and ER stress was induced, indicating that thyroid function was directly impaired. We also observed pronounced morphological 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 signaling initial translatability. These studies lay the groundwork for novel obesity therapies that tackle hypothyroidism—which are much-needed, as no current obesity treatment works for everyone. Overall design: To investigate the effects of overnutrition on the thyroid, we placed C57Bl/6J mice on a high-fat diet and sucrose water, whereas control mice were given a chow diet. Thyroids were collected at two timepoints for differential gene expression analysis and gene set enrichment analysis based on bulk RNA-sequencing data from 4 mouse thyroids/group/timepoint.