Bone Morphogenetic Protein-3b Deficiency Induces Metabolic Syndrome and Modulates Adipogenesis

Introduction: Bone morphogenetic proteins (BMPs) are mediators in a wide range of cellular functions, including the regulation of cell metabolism. The objective of this study was to investigate the effects of BMP-3b, a glycoprotein synthetized and secreted by adipose tissue, on cardiovascular risk factors. Methods: BMP-3b knock-out (KO) and age-matched male and female wild-type (WT) mice were weighed weekly until 6 months of age. At 6 months, fasting levels of total cholesterol, HDL-C and triglycerides were measured and glucose and insulin tolerance tests were performed. Telemetry was used to determine blood pressure and heart rate in anesthetized mice. Echocardiograms were performed under light sedation (isoflurane 1%). Mice were sacrificed and tissues were resected for gene expression analysis by qPCR. Transient transfections were performed in 3T3-L1 cells to study the interactions of BMP-3b and the C/ebp α promoter. Results: BMP3b KO mice gained more weight than WT mice. The plasma levels of total cholesterol, HDL and triglycerides were higher in BMP-3b KO mice than in WT mice. Insulin and glucose tolerant tests reveal insulin resistance and glucose intolerance in BMP-3b KO mice compared to WT mice. The basal heart rate was higher in BMP-3b KO mice than in WT mice, but no differences were observed in blood pressure. Echocardiography revealed a decrease in relative wall thickness (RWT) and left ventricular ejection fraction (LVEF), and an increase in the left ventricle end diastolic volume (LVEDV) in BMP-3b KO mice, demonstrating eccentric remodeling. Expression of genes ( Pparγ and C/ebpα ) involved in adipogenesis in white adipose tissue was higher in BMP-3b KO mice than in WT controls. Finally, transient transfection assays with 3T3-L1 cells showed that BMP-3b modulates C/ebpα promoter activity. Conclusions: The results of this study suggest that BMP-3b has an important role in the regulation of age-related weight gain, glucose metabolism and LV remodeling. Interventions that increase the level or function of BMP-3b may protect the heart from the adverse effects of cardiovascular risk factors and pathological cardiac remodeling.