Obesity is a major health problem worldwide, given its growing incidence and its association with a variety of comorbidities. Weight gain results from an increase in energy intake without a concomitant increase in energy expenditure. To combat the obesity epidemic, many studies have focused on the pathways underlying satiety and hunger signaling, while other studies have concentrated on the mechanisms involved in energy expenditure, most notably adaptive thermogenesis. Hypothyroidism in humans is typically associated with a decreased basal metabolic rate, lower energy expenditure, and weight gain. However, hypothyroid mouse models have been reported to have a leaner phenotype than euthyroid controls. To elucidate the mechanism underlying this phenomenon, we used a drug-free mouse model of hypothyroidism: mice lacking the sodium/iodide symporter (NIS), the plasma membrane protein that mediates active iodide uptake in the thyroid. In addition to being leaner than euthyroid mice, owing in part to reduced food intake, these hypothyroid mice show signs of compensatory up-regulation of the skeletal-muscle adaptive thermogenic marker sarcolipin, with an associated increase in fatty acid oxidation (FAO). Neither catecholamines nor thyroid-stimulating hormone (TSH) are responsible for sarcolipin expression or FAO stimulation; rather, thyroid hormones are likely to negatively regulate both processes in skeletal muscle. Our findings indicate that hypothyroidism in mice results in a variety of metabolic changes, which collectively lead to a leaner phenotype. A deeper understanding of these changes may make it possible to develop new strategies against obesity.

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The rate of obesity is steadily increasing in the United States and around the world. This is a major health concern, as obesity is associated with multiple leading causes of death, including heart disease, stroke, type 2 diabetes, and a subset of cancers [1]. Reduced thermogenesis causes fat and weight gain, whereas increased thermogenesis promotes weight and fat loss [2-5]. Therefore, stimulating adaptive thermogenesis is a promising approach to treating the obesity epidemic. However, current avenues of research have yet to identify a thermogenic target that could be used to efficaciously promote weight loss. The sodium/iodide symporter (NIS) is the key plasma membrane protein that mediates the sodium-dependent active transport of iodide into the thyroid follicular cells, the first step in the biosynthesis of the thyroid hormones (THs) [6]. Using a drug-free model of severe hypothyroidism (mice that are knockouts for NIS placed on a low-iodide diet), we found that these mice do not gain weight and exhibit a trend towards higher energy expenditure than is exhibited by a model of mild hypothyroidism (wild-type mice on a low-iodide diet). Severely hypothyroid mice exhibit significantly increased expression of markers of adipose tissue and skeletal muscle adaptive thermogenesis at room temperature (22°C). These mice may upregulate thermogenic mechanisms to compensate for reduced basal metabolism. This hypothesis is supported by the fact that severely hypothyroid mice are cold intolerant when transferred from thermoneutrality to a 4°C cold challenge, despite increased levels of thermogenic markers. Our results are consistent with the hypothesis that severely hypothyroid mice upregulate thermogenic mechanisms to maintain homeostasis, which ultimately protects them from weight gain. References: 1. Prevention, C. f. D. C. a. Overweight & Obesity. (2017). 2. Bal, N. C., et al., Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat Med 18 , 1575-1579, (2012). 3. Feldmann, H. M., et al., UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 9 , 203-209, (2009). 4. Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat Med 19 , 1252-1263, (2013). 5. Lin, J. Z., et al., Pharmacological Activation of Thyroid Hormone Receptors Elicits a Functional Conversion of White to Brown Fat. Cell Rep 13 , 1528-1537, (2015). 6. Ravera, S., et al., The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications. Annu Rev Physiol 79 , 261-289, (2017).

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