Uncovering the mechanisms of acute overnutrition-induced thyroid dysfunction

Obesity affects 40% of the U.S. population and rising, and is one of today’s biggest public health concerns. Losing weight is challenging, and maintaining weight loss even more so, owing to the many biochemical and hormonal changes that occur in the pathogenesis of obesity, some of which do not reverse after weight loss. Thyroid hormones (THs) have a large impact on whole-body energy balance. Their synthesis and release by the thyroid are finely regulated by central mechanisms to control serum TH levels and ensure adequate TH availability for target tissues. THs are also regulated by nutrient sensing, so that their levels modulate cellular energy expenditure to match energy availability. Given the reciprocal and fine-tuned relationship between THs and energy balance, one would expect strong upregulation of TH levels to counteract diet-induced weight gain (DIWG), but this is not the case. In fact, overnutrition induces mild hypothyroidism and impairs thyroid function, additionally causing significant histological changes. An adequate TH supply from the thyroid is critical for proper TH signaling, particularly in metabolic tissues that must generate higher levels of active T3 from the prohormone T4 than are available from the bloodstream. Moreover, substantial evidence links impaired thyroid function to DIWG and other metabolic dysfunctions, albeit with some controversy stemming mainly from poor study designs. Even so, this controversy underscores the importance of further investigation in this field, and neither the effects of overnutrition on thyroid histology and function nor the mechanism(s) underlying diet-induced TH abnormalities have been sufficiently investigated. We hypothesize that overnutrition impairs thyroid function, in part by perturbing intrathyroidal TSH signaling and inducing cellular stress responses, leading to an inadequate TH supply that further exacerbates DIWG.