title: Thyrotropin and obesity: increased adipose triglyceride content through glycerol-3-phosphate acyltransferase 3.
abstract: Epidemiological evidence indicates that thyrotropin (TSH) is positively correlated with the severity of obesity. However, the mechanism remains unclear. Here, we show that TSH promoted triglyceride (TG) synthesis in differentiated adipocytes in a thyroid hormone-independent manner. Mice with subclinical hypothyroidism, which is characterized by elevated serum TSH but not thyroid hormone levels, demonstrated a 35% increase in the total white adipose mass compared with their wild-type littermates. Interestingly, Tshr KO mice, which had normal thyroid hormone levels after thyroid hormone supplementation, resisted high-fat diet-induced obesity. TSH could directly induce the activity of glycerol-3-phosphate-acyltransferase 3 (GPAT3), the rate-limiting enzyme in TG synthesis, in differentiated 3T3-L1 adipocytes. However, following either the knockdown of Tshr and PPARγ or the constitutive activation of AMPK, the changes to TSH-triggered GPAT3 activity and adipogenesis disappeared. The over-expression of PPARγ or the expression of an AMPK dominant negative mutant reversed the TSH-induced changes. Thus, TSH acted as a previously unrecognized master regulator of adipogenesis, indicating that modification of the AMPK/PPARγ/GPAT3 axis via the TSH receptor might serve as a potential therapeutic target for obesity.
authors.affiliation: 1] Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China [2] Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors.forename: Shizhan
authors.initials: S
authors.lastname: Ma
authors.affiliation: 1] Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China [2] Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Jing
authors.affiliation: 1] Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China [2] Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: 1] Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China [2] Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Zhou
authors.affiliation: 1] Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China [2] Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Song
authors.affiliation: 1] Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China [2] Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Yu
authors.affiliation: 1] Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China [2] Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Jiang
authors.affiliation: 1] Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China [2] Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: 1] Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China [2] Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1] Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China [2] Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Guan
authors.affiliation: 1] Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China [2] Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhao
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D052436:Adipose Tissue, White / Q000378:metabolism* / Q000473:pathology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism*; D007037:Hypothyroidism / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism / Q000473:pathology*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013972:Thyrotropin / Q000097:blood* / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D047495:PPAR gamma; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011989:Receptors, Thyrotropin; D014280:Triglycerides; D013972:Thyrotropin; D005992:Glycerol-3-Phosphate O-Acyltransferase; D055372:AMP-Activated Protein Kinases