SAT-563 Nonshivering Thermogenesis as a Compensatory Mechanism for Reduced Metabolism in Severely Hypothyroid Mice

ABSTRACT 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 Med18, 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 Metab9, 203-209, (2009). 4. Harms, M. & Seale, P. Brown and beige fat: development, function and therapeutic potential. Nat Med19, 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 Rep13, 1528-1537, (2015). 6. Ravera, S., et al., The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications. Annu Rev Physiol79, 261-289, (2017).