title: Angiopoietin-like 2, a circadian gene, improves type 2 diabetes through potentiation of insulin sensitivity in mice adipocytes.
abstract: Angiopoietin-like (Angptl)2, a member of the Angptl protein family, is predominantly secreted from adipose tissue and the heart. Here, we demonstrate that the expression of Angptl2 in epididymal adipose tissue of C57BL/6J mice shows pulsatility and circadian rhythmicity and that the rhythmicity was disrupted in high-fat-fed and leptin receptor-deficient diabetic db/db mice with insulin resistance. To investigate whether the reduction in Angptl2 expression was related to the progression of diabetes, we treated db/db mice with recombinant Angptl2 for 4 wk during the peak period of Angptl2 expression in C57BL/6J mice. Angptl2-treated mice showed decreases in plasma glucose, insulin, triglyceride, and fatty acid levels and an increase in plasma adiponectin, a therapeutic regulator of insulin resistance, leading to improvements in glucose tolerance. In cultured adipocytes, recombinant Angptl2 increased adiponectin expression and stimulated insulin sensitivity partially by reducing the levels of tribbles homolog 3, a specific Akt kinase inhibitory protein. Conversely, Angptl2 small interfering RNA reduced adiponectin expression, resulting in insulin resistance. In preadipocytes, treatment with Angptl2 small interfering RNA inhibited differentiation to adipocytes and reduced adiponectin expression. Taken together, our results suggest that replenishment of Angptl2 stimulates insulin sensitivity and improves the type 2 diabetic state.
authors.affiliation: Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan. masashi-kitazawa@aist.go.jp
authors.forename: Masashi
authors.initials: M
authors.lastname: Kitazawa
authors.forename: Mamoru
authors.initials: M
authors.lastname: Nagano
authors.forename: Koh-Hei
authors.initials: KH
authors.lastname: Masumoto
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Shigeyoshi
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hashimoto
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis; D052242:Adiponectin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D005786:Gene Expression Regulation; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000627:therapeutic use
chemical_list: C485792:ANGPTL2 protein, human; D052242:Adiponectin; C499919:Adipoq protein, mouse; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; D018797:Cell Cycle Proteins; D056925:Circadian Rhythm Signaling Peptides and Proteins; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054411:Receptors, Leptin; D011994:Recombinant Proteins; C474830:TRB3 protein, mouse; C515447:leptin receptor, mouse