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Modulation of Bone Morphogenetic Protein-9 Expression and Processing by Insulin, Glucose, and Glucocorticoids: Possible Candidate for Hepatic Insulin-Sensitizing Substance

Department of Biological Sciences (L.C.C.), Federal University of São Paulo, 04023-900 São Paulo, Brazil; and Department of Physiology and Biophysics (G.F.A., T.D.C., E.H.A., D.C.B., J.C.-B., R.C., S.B.), Institute of Biomedical Sciences, University of São Paulo, 05508-900 São Paulo, Brazil

Address all correspondence and requests for reprints to: Silvana Bordin, Departamento de Fisiologia e Biofísica, Universidade de São Paulo, Av Lineu Prestes, 1524-ICB 1-Sala 125, 05508-900 São Paulo, Brasil. E-mail: sbordin{at}icb.usp.br.

Bone morphogenetic protein 9 (BMP-9), a member of the TGF-β superfamily predominantly expressed in nonparenchymal liver cells, has been demonstrated to improve glucose homeostasis in diabetic mice. Along with this therapeutic effect, BMP-9 was proposed as a candidate for the hepatic insulin-sensitizing substance (HISS). Whether BMP-9 plays a physiological role in glucose homeostasis is still unknown. In the present study, we show that BMP-9 expression and processing is severely reduced in the liver of insulin-resistant rats. BMP-9 expression and processing was directly stimulated by in situ exposition of the liver to the combination of glucose and insulin and oral glucose in overnight fasted rats. Additionally, prolonged fasting (72 h) abrogated refeeding-induced BMP-9 expression and processing. Previous exposition to dexamethasone, a known inductor of insulin resistance, reduced BMP-9 processing stimulated by the combination of insulin and glucose. Finally, we show that neutralization of BMP-9 with an anti-BMP-9 antibody induces glucose intolerance and insulin resistance in 12-h fasted rats. Collectively, the present results demonstrate that BMP-9 plays an important role in the control of glucose homeostasis of the normal rat. Additionally, BMP-9 is expressed and processed in an HISS-like fashion, which is impaired in the presence of insulin resistance. BMP-9 regulation according to the feeding status and the presence of diabetogenic factors reinforces the hypothesis that BMP-9 might exert the role of HISS in glucose homeostasis physiology.