Abstract 14693: Deficiency of Bone Morphogenetic Protein-3b Increases the Activity of the C/ebpα Promoter and Adipogenesis

IntroductionBone morphogenetic proteins (BMP) are critical for the regulation of the endocrine system and cardiovascular (CV) structure and function. The objective of this study was to investigate whether Bmp3b, a glycoprotein synthetized and secreted by adipose tissue, is necessary to regulate adipogenesis, glucose and lipid metabolism, and cardiac structure and function. The interaction of Bmp3b with C/ebpα and Pparγ pathways was studied.MethodsBmp3b knockout (Bmp3b) and age-matched male and female wild-type (WT) mice were weighed weekly until 6 months of age. At 6 months, cholesterol and triglycerides were measured and glucose and insulin tolerance tests were performed. Telemetry was used to determine blood pressure and heart rate. Echocardiograms were performed under light sedation. Mice were sacrificed and adipose tissue was harvested for gene expression analysis. Transfections were performed in 3T3-L1 cells to study C/ebpα promoter activity.ResultsBmp3b mice gained more weight than WT mice throughout the follow-up period. The plasma levels of cholesterol and triglycerides were higher in Bmp3b mice than in WT mice. Insulin resistance and glucose intolerance were present in Bmp3b mice. The basal heart rate was higher in Bmp3b mice than in WT mice, but no difference was observed in blood pressure. Echocardiography revealed a decrease in relative wall thickness (RWT) and left ventricular ejection fraction (LVEF), and an increase in left ventricle end diastolic volume (LVEDV) in Bmp3b mice, demonstrating eccentric remodeling. The expression of genes (Pparγ and C/ebpα) involved in adipogenesis was higher in the adipose tissue of Bmp3b mice than in WT mice. Transient transfection assays in 3T3-L1 cells showed that Bmp3b treatment decreased the activity of the C/ebpα promoter, and Bmp3b inhibition by siRNA increased C/ebpα promoter activity.ConclusionsBmp3b is necessary for the maintenance of homeostasis in age-related weight gain, glucose and lipid metabolism, and LV remodeling and function. Bmp3b deficiency increases C/ebpα promoter activity, activating a major adipogenesis-promoting pathway. Interventions that increase the level or function of Bmp3b may decrease CV risk factors and their impact on the heart.