BMPs As New Insulin Sensitizers: Enhanced Glucose Uptake in Mature 3T3-L1 Adipocytes Via PPARγ and GLUT4 Upregulation

Overview

Journal Sci Rep

Specialty Science

Date 2017 Dec 10

PMID 29222456

Citations 32

Authors

Isabelle Schreiber

Gina Dorpholz

Claus-Eric Ott

Bjort Kragesteen

Nancy Schanze

Cory Thomas Lee

Josef Kohrle

Stefan Mundlos

Karen Ruschke

Petra Knaus

Affiliations

Soon will be listed here.

Abstract

Insulin-resistance is the main cause of type 2 diabetes. Here we describe the identification and characterization of BMP2 and BMP6 as new insulin-sensitizing growth factors in mature adipocytes. We show that BMP2 and BMP6 lead to enhanced insulin-mediated glucose uptake in both insulin-sensitive and -insensitive adipocytes. We exclude a direct effect of BMP2 or BMP6 on translocation of GLUT4 to the plasma membrane and demonstrate that these BMPs increase GLUT4 protein levels equipotent to Rosiglitazone. BMPs induce expression of PPARγ as the crucial mediator for the insulin-sensitizing effect. A comprehensive RNA-Seq analysis in mature adipocytes revealed regulation of both BMP/Smad and PPARγ target genes. The effects of BMP2 and BMP6 are not completely redundant and include regulation of genes involved in glucose and fatty acid metabolism and adipokine expression. Collectively, these findings suggest the BMP2 and BMP6 pathway(s) as promising new drug targets to treat insulin resistance.

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References

Hata K, Nishimura R, Ikeda F, Yamashita K, Matsubara T, Nokubi T . Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor gamma during bone morphogenetic protein 2-induced adipogenesis. Mol Biol Cell. 2003; 14(2):545-55. PMC: 149991. DOI: 10.1091/mbc.e02-06-0356. View

Bluher M . Adipokines - removing road blocks to obesity and diabetes therapy. Mol Metab. 2014; 3(3):230-40. PMC: 3986498. DOI: 10.1016/j.molmet.2014.01.005. View

Bugge A, Dib L, Collins S . Measuring respiratory activity of adipocytes and adipose tissues in real time. Methods Enzymol. 2014; 538:233-47. DOI: 10.1016/B978-0-12-800280-3.00013-X. View

Bauer S, Grossmann S, Vingron M, Robinson P . Ontologizer 2.0--a multifunctional tool for GO term enrichment analysis and data exploration. Bioinformatics. 2008; 24(14):1650-1. DOI: 10.1093/bioinformatics/btn250. View

Richter E, Hargreaves M . Exercise, GLUT4, and skeletal muscle glucose uptake. Physiol Rev. 2013; 93(3):993-1017. DOI: 10.1152/physrev.00038.2012. View

Jin W, Takagi T, Kanesashi S, Kurahashi T, Nomura T, Harada J . Schnurri-2 controls BMP-dependent adipogenesis via interaction with Smad proteins. Dev Cell. 2006; 10(4):461-71. DOI: 10.1016/j.devcel.2006.02.016. View

Somwar R, Koterski S, Sweeney G, Sciotti R, Djuric S, Berg C . A dominant-negative p38 MAPK mutant and novel selective inhibitors of p38 MAPK reduce insulin-stimulated glucose uptake in 3T3-L1 adipocytes without affecting GLUT4 translocation. J Biol Chem. 2002; 277(52):50386-95. DOI: 10.1074/jbc.M205277200. View

Urist M . Bone: formation by autoinduction. Science. 1965; 150(3698):893-9. DOI: 10.1126/science.150.3698.893. View

Knutson V, Balba Y . 3T3-L1 adipocytes as a cell culture model of insulin resistance. In Vitro Cell Dev Biol Anim. 1997; 33(2):77-81. DOI: 10.1007/s11626-997-0025-2. View

10.

Weems J, Griesel B, Olson A . Class II histone deacetylases downregulate GLUT4 transcription in response to increased cAMP signaling in cultured adipocytes and fasting mice. Diabetes. 2012; 61(6):1404-14. PMC: 3357296. DOI: 10.2337/db11-0737. View

11.

Yang L, Chang C, Sun Z, Madsen D, Zhu H, Padkjaer S . GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med. 2017; 23(10):1158-1166. DOI: 10.1038/nm.4394. View

12.

Qian S, Tang Y, Li X, Liu Y, Zhang Y, Huang H . BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci U S A. 2013; 110(9):E798-807. PMC: 3587258. DOI: 10.1073/pnas.1215236110. View

13.

Liao W, Audrey Nguyen M, Yoshizaki T, Favelyukis S, Patsouris D, Imamura T . Suppression of PPAR-gamma attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab. 2007; 293(1):E219-27. DOI: 10.1152/ajpendo.00695.2006. View

14.

Nakachi Y, Yagi K, Nikaido I, Bono H, Tonouchi M, Schonbach C . Identification of novel PPARgamma target genes by integrated analysis of ChIP-on-chip and microarray expression data during adipocyte differentiation. Biochem Biophys Res Commun. 2008; 372(2):362-6. DOI: 10.1016/j.bbrc.2008.05.037. View

15.

Huang H, Song T, Li X, Hu L, He Q, Liu M . BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci U S A. 2009; 106(31):12670-5. PMC: 2722335. DOI: 10.1073/pnas.0906266106. View

16.

Hiepen C, Yadin D, Rikeit P, Dorpholz G, Knaus P . Actions from head to toe: An update on Bone/Body Morphogenetic Proteins in health and disease. Cytokine Growth Factor Rev. 2016; 27:1-11. DOI: 10.1016/j.cytogfr.2015.12.006. View

17.

Bell B, Rahmouni K . Leptin as a Mediator of Obesity-Induced Hypertension. Curr Obes Rep. 2016; 5(4):397-404. PMC: 5119542. DOI: 10.1007/s13679-016-0231-x. View

18.

Chen C, Grzegorzewski K, Barash S, Zhao Q, Schneider H, Wang Q . An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis. Nat Biotechnol. 2003; 21(3):294-301. DOI: 10.1038/nbt795. View

19.

Berger J, Biswas C, Vicario P, Strout H, SAPERSTEIN R, Pilch P . Decreased expression of the insulin-responsive glucose transporter in diabetes and fasting. Nature. 1989; 340(6228):70-2. DOI: 10.1038/340070a0. View

20.

Frost S, Lane M . Evidence for the involvement of vicinal sulfhydryl groups in insulin-activated hexose transport by 3T3-L1 adipocytes. J Biol Chem. 1985; 260(5):2646-52. View