OR29-04 High-fat Diet Decreases mTORC1 Activity In Thyrocytes And Impairs Thyroid Function

Abstract C.L. Rossetti: None. C. Pintado: None. R.A. Louzada: None. E. Bernal-Mizrachi: None. J.P. Saar Werneck de Castro: None. Individuals suffering from obesity or insulin resistance (IR) have a higher prevalence of hypothyroidism. However, the exact mechanisms through which overnutrition affects thyroid function remain unclear. The mechanistic target of rapamycin complex 1 (mTORC1) senses and integrates hormonal/growth factor signaling and nutrient cues to regulate cellular function. The mTORC1 pathway is dysregulated in metabolic tissues like the liver and pancreas during metabolic diseases. To investigate the impact of obesity and IR on mTORC1 activity and thyroid function, we fed 12-week-old male C57BL/6 mice with either a regular diet (RD) or a high-fat diet (HFD - 60% of calories derived from fat) for three weeks. HFD mice exhibited weight gain, impaired glucose tolerance, insulin resistance, and hyperinsulinemia. We observed that the HFD led to a decrease in thyroid weight and plasma total T4, although TSH levels were normal. Analysis of thyroid mRNA expression revealed signs of hypothyroidism, with increased expression of NIS, TPO, and Dio1. However, the expression of MCT8, TSH, and Insulin receptors was normal in the HFD group. NIS protein levels were also 2-fold increased. NOX4 and DUOx1 mRNA levels, as well as the protein levels of NQ01, decreased in the HFD group. This suggests a reduction in the production of reactive oxygen species (ROS) in the thyroid after HFD. Notably, mTORC1 activity, as determined by the phosphorylation of the ribosomal S6 protein (pS6), dropped to 30% of control levels. This implies that nutrient excess may be impairing mTORC1 activation in the thyroid gland, potentially underlying the thyroid dysfunction observed in HFD. Next, by deleting the TSC2 gene in thyrocytes upon tamoxifen administration (iTSC2KO), an expected increase in thyroid mTORC1 activity was observed (3.6-fold in pS6) along with a 1.6-fold increase in thyroid weight in RD. Remarkably, when on HFD, iTSC2KO showed a 1.9-fold increase in mTORC1 activity and a 1.3-fold increase in thyroid weight, strongly suggesting that HFD promotes a decrease in the mTORC1 activity and consequently tissue growth even in potent animal model of mTORC1 overactivation. In conclusion, our findings suggest that diet-induced obesity may impair mTORC1 activity in the thyroid gland, leading to thyroid dysfunction. Saturday, June 1, 2024