Cross Talk between Insulin and Bone Morphogenetic Protein Signaling Systems in Brown Adipogenesis

Abstract

Both insulin and bone morphogenetic protein (BMP) signaling systems are important for adipocyte differentiation. Analysis of gene expression in BMP7-treated fibroblasts revealed a coordinated change in insulin signaling components by BMP7. To further investigate the cross talk between insulin and BMP signaling systems in brown adipogenesis, we examined the effect of BMP7 in insulin receptor substrate 1 (IRS-1)-deficient brown preadipocytes, which exhibit a severe defect in differentiation. Treatment of these cells with BMP7 for 3 days prior to adipogenic induction restored differentiation and expression of brown adipogenic markers. The high level of adipogenic inhibitor preadipocyte factor 1 (Pref-1) in IRS-1-null cells was markedly reduced by 3 days of BMP7 treatment, and analysis of the 1.3-kb pref-1 promoter revealed 9 putative Smad binding elements (SBEs), suggesting that BMP7 could directly suppress Pref-1 expression, thereby allowing the initiation of the adipogenic program. Using a series of sequential deletion mutants of the pref-1 promoter linked to the luciferase gene and chromatin immunoprecipitation, we demonstrate that the promoter-proximal SBE (−192/−184) was critical in mediating BMP7's suppressive effect on pref-1 transcription. Together, these data suggest cross talk between the insulin and BMP signaling systems by which BMP7 can rescue brown adipogenesis in cells with insulin resistance.

Supplemental material for this article may be found at http://mcb.asm.org/.

This work was supported in part by grants R01 DK077097, R21 DK070722, and UL1 RR 025758-01 from NIH (Harvard Catalyst/The Harvard Clinical and Translational Science Center) and research grants from the Eli Lilly Research Foundation and Harvard Stem Cell Institute (to Y.-H.T.), by the Joslin Diabetes and Endocrinology Research Center (P30DK036836 from the NIDDK), the Danish Natural Science Research Council, the Novo Nordisk Foundation, and the Carlsberg Foundation (to K.K.).

We acknowledge A. Lassar (Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School) for providing the Smad expression constructs and H. S. Sul for providing the pref-1 promoter vector. We thank C. R. Kahn for input on initiation of this project; S. Russell for helpful discussions on pref-1 promoter sequences; J. Schroeder, Y.-C. Lai, and J. Li for technical assistance; and K. Townsend and L. McDougall for critical reading of the manuscript.

We declare no competing financial interests.