TSH Promotes Adiposity by Inhibiting the Browning of White Fat

Background: Adiposity is caused by an imbalance between energy intake and consumption. Promotion of the browning of white fat increases energy expenditure and could be a promising therapy for adiposity. Thyroid-stimulating hormone (TSH) has been confirmed to positively correlate with adiposity. However, the putative connection between TSH and white adipose browning has never been explored. In this study, we sought to assess the effect of TSH on white adipose tissue browning and energy metabolism. Methods: Subclinical hypothyroidism mice, thyroid-specific Tshr-knockout mice injected with TSH, adipocyte-specific Tshr-knockout mice, global Tshr-knockout mice and their littermates were subjected to morphological, physiological, genetic or protein expression analyses and metabolic cages to determine the role of TSH on the browning of white adipose tissue and metabolism. To activate thermogenesis, some mice were exposed to cold condition for 4 weeks. 3T3-L1 cells and primary SVF cells were used to verify the effects of TSH on the browning of white adipocytes and its mechanism. Findings: We show that TSH decreases energy expenditure, promotes body weight gain, impairs glucose tolerance and lipid metabolism in subclinical hypothyroidism mice and thyroid-specific Tshr-knockout mice injected with TSH. Adipose-specific or global knockout of Tshr decreases adiposity, resists diet-induced obesity and increases energy expenditure. The knockout of Tshr markedly promotes the development of beige adipocytes and increases expression of UCP1 and other thermogenic genes in both epididymal and inguinal subcutaneous white fat via a mechanism that likely involves AMPK/PRDM16/PGC1α. Interpretation: Our results reveal an important role of TSH in regulating energy balance and adiposity by inhibiting the browning of white fat. Funding: This work was supported by grants from the National Natural Science Foundation (81400828) and the Natural Science Foundation of Shandong Province (ZR2014HQ057). This study was also supported by Projects of the Medical and Health Technology Development Program in Shandong Province (2016WS0427) and Shandong Key R&D Program (2017GSF18129). Declaration of Interest: The authors have no competing financial interests to declare. Ethical Approval: All animal experimental protocols were approved by the Animal Care Committee of School of Medicine, Shandong University.