Novel Effects of Obesity on Thyroid Pathophysiology and Thyroid Hormone Action

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cellular and Molecular Physiology

First Advisor

Carrasco, Nancy

Abstract

Thyroid hormones are key regulators of basal metabolic rate and nutrient metabolism. They are regulated by the hypothalamic-pituitary-thyroid axis and the deiodinases in a coordinated, whole-body manner to elegantly match T3-mediated energy expenditure to energy availability. Hypothyroidism is marked by a low metabolic rate and various metabolic ailments. It has long been blamed for obesity, a disease characterized by energy imbalance and metabolic disturbances that affects >40% of the U.S. population. A great deal of research has focused on the effects of thyroid status on obesity, but much less is known about obesity’s effects on thyroid function, though it is increasingly being understood how deleteriously obesity disrupts endocrine function. The link between thyroid hormone dysregulation and obesity is a strong one, and emerging evidence suggests that a shift in paradigm, whereby obesity is taken to be the driving factor, is warranted, bolstered by a growing number of studies demonstrating that weight loss improves thyroid function. Thus, we purposed to determine the direct effects of obesity on the thyroid both histologically and biochemically, as well as its effects on deiodinase activity and T3 action.To do so, we used a mouse model of diet-induced obesity. Strikingly, within 3 weeks, overnutrition induced hypothyroidism, characterized by decreased serum T4, increased thyroid stimulating hormone levels, and goiter—all of which progressively worsened. Concomitantly, thyroidal T4 levels significantly decreased within 10 days, and thyroidal T3 levels eventually declined as well, indicating that thyroid function had been directly impaired. Furthermore, we found that overnutrition induced endoplasmic reticulum stress—limiting synthesis of the thyroid hormone precursor protein thyroglobulin—and changes in mitochondria and lipid droplets. We did not find evidence to support increased thyroid hormone degradation as a mechanism for overnutrition-induced hypothyroidism. On the contrary, we discovered that diet-induced obesity lowers the whole-body T4-to-T3 conversion rate (an activating reaction), rendering the mice resistant to T4 and causing them to expend less energy. These dysfunctions were accompanied by pronounced histological and vascular changes in the thyroid, which would promote thyroid activity—albeit insufficiently, according to our results. We also reported, for the first time, similar vascular changes in human thyroids that strongly correlate with body mass index. Collectively, our findings show that overnutrition deals a double blow to thyroid hormone biosynthesis and action, despite the struggling thyroid’s best efforts to adapt. Fortunately, thyroid dysfunction in mice can be reversed when they lose weight—but current weight loss therapies are not successful for all patients. Our studies lay the pathophysiological groundwork for developing targeted therapies for hypothyroidism secondary to obesity.

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