SAT-550 High Fat Diet-Induced ER Stress Affects Hypothyroidism

Recent studies revealed the emerging role of excess uptake of lipids in the development of hypothyroidism. Both dietary high-fat lard intake in rats and diet-induced obese mice displayed thyroid hypofunction (1,2). However, the underlying mechanism is largely unknown. We investigated the effect of high fat diet (HFD) on thyroid function and the role of endoplasmic reticulum (ER) in HFD induced hypothyroidism. Male Sprague Dawley rats were fed with HFD or control diet (CD) for 18 weeks. HFD rats showed increased serum TSH (n=15-16) and decreased T4 (n=15-16) compared to CD rats. Thyroid function was also evaluated by thyroid radioiodine uptake for 24 hours in vivo. Consistently, HFD decreased thyroid iodine uptake (-60%, n=5). To understand the molecular mechanism, we assessed the expression of proteins critical to thyroid production via Western blotting. Compared to CD, HFD rats showed significantly decreased thyroglobulin (Tg) (-40%, n=4), whereas TPO and NIS showed no difference. Meanwhile, luminal swelling of ER in thyroid epithelial cell of HFD rats was observed via transmission electron microscopy. Furthermore, We found PERK/eIF2a/ATF4 -- one of three traditional UPR pathways triggered under ER stress -- was activated in HFD rat thyroid glands compared to CD (n=4). In vitro, ER stress was induced in primary human thyrocytes by palmitate. Under the treatment of palmitate, Tg was degraded more rapidly than the control, indicating the activating of the ER-associated protein degradation pathway under ER stress. In addition, alleviation of ER stress by applying 4-phenyl butyric acid (4-PBA) in HFD rats or by the withdrawal of HFD improved the decrease of Tg (n=4-6) and thyroid function (n=3-6). In conclusion, we demonstrate that ER stress mediates the HFD induced hypothyroidism, probably by impairing the production of Tg, and attenuation of ER stress improves thyroid function. Reference: (1) Shao et al., Acta Pharmacol Sin 2014, 35: 1411-1420. (2) Lee et al., Endocrinology 2015, 156: 1181-1193. Conflict of interest: The authors declare they have no conflicts of interest. Sources of Research Support: National Natural Science Foundation of China (81430020, 81230018, 81600604, 81300644, and 81670720) and the Natural Science Foundation of Shandong Province (ZR2016HB07).