title: Loss of FTO in adipose tissue decreases Angptl4 translation and alters triglyceride metabolism.
abstract: A common variant of the FTO (fat mass- and obesity-associated) gene is a risk factor for obesity. We found that mice with an adipocyte-specific deletion of FTO gained more weight than control mice on a high-fat diet. Analysis of mice lacking FTO in adipocytes fed a normal diet or adipocytes from these mice revealed alterations in triglyceride metabolism that would be expected to favor increased fatty acid storage by adipose tissue. Mice lacking FTO in adipocytes showed increased serum triglyceride breakdown and clearance, which was associated with lower serum triglyceride concentrations. In addition, lipolysis in response to β-adrenergic stimulation was decreased in adipocytes and ex vivo adipose explants from the mutant mice. FTO is a nucleic acid demethylase that removes N(6)-methyladenosine (m(6)A) from mRNAs. We found that FTO bound to Angptl4, which encodes an adipokine that stimulates intracellular lipolysis in adipocytes. Unexpectedly, the adipose tissue of fasted or fed mice lacking FTO in adipocytes had greater Angptl4 mRNA abundance. However, after high-fat feeding, the mutant mice had less Angptl4 protein and more m(6)A-modified Angptl4 than control mice, suggesting that lack of FTO prevented the translation of Angptl4. Injection of Angptl4-encoding adenovirus into mice lacking FTO in adipocytes restored serum triglyceride concentrations and lipolysis to values similar to those in control mice and abolished excessive weight gain from a high-fat diet. These results reveal that FTO regulates fatty acid mobilization in adipocytes and thus body weight in part through posttranscriptional regulation of Angptl4.
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 33302, Taiwan. cwang@ocean.ag.
authors.forename: Chao-Yung
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 33302, Taiwan.
authors.forename: Shian-Sen
authors.initials: SS
authors.lastname: Shie
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 33302, Taiwan.
authors.forename: Ming-Shien
authors.initials: MS
authors.lastname: Wen
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 33302, Taiwan.
authors.forename: Kuo-Chun
authors.initials: KC
authors.lastname: Hung
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 33302, Taiwan.
authors.forename: I-Chang
authors.initials: IC
authors.lastname: Hsieh
authors.affiliation: Department of General Surgery, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 33302, Taiwan.
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.affiliation: Department of Cardiology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 33302, Taiwan.
authors.forename: Delon
authors.initials: D
authors.lastname: Wu
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000096:biosynthesis*; D000818:Animals; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D007652:Oxo-Acid-Lyases / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism*
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D014280:Triglycerides; D006899:Mixed Function Oxygenases; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D007652:Oxo-Acid-Lyases