ABSTRACT
Expression of bone morphogenetic protein 4 (BMP4) in adipocytes of white adipose tissue (WAT) produces "white adipocytes" with characteristics of brown fat and leads to a reduction of adiposity and its metabolic complications. Although BMP4 is known to induce commitment of pluripotent stem cells to the adipocyte lineage by producing cells that possess the characteristics of preadipocytes, its effects on the mature white adipocyte phenotype and function were unknown. Forced expression of a BMP4 transgene in white adipocytes of mice gives rise to reduced WAT mass and white adipocyte size along with an increased number of a white adipocyte cell types with brown adipocyte characteristics comparable to those of beige or brite adipocytes. These changes correlate closely with increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. Conversely, BMP4-deficient mice exhibit enlarged white adipocyte morphology and impaired insulin sensitivity. We identify peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as the target of BMP signaling required for these brown fat-like changes in WAT. This effect of BMP4 on WAT appears to extend to human adipose tissue, because the level of expression of BMP4 in WAT correlates inversely with body mass index. These findings provide a genetic and metabolic basis for BMP4's role in altering insulin sensitivity by affecting WAT development.
Subject(s)
Adipose Tissue, Brown/metabolism , Adipose Tissue, White/metabolism , Bone Morphogenetic Protein 4/genetics , Bone Morphogenetic Protein 4/metabolism , Energy Metabolism , Glucose/metabolism , Homeostasis , 3T3-L1 Cells , Activating Transcription Factor 2/metabolism , Adipocytes, Brown/drug effects , Adipocytes, Brown/metabolism , Adipocytes, Brown/pathology , Adipocytes, White/drug effects , Adipocytes, White/enzymology , Adipocytes, White/pathology , Adipose Tissue, Brown/drug effects , Adipose Tissue, Brown/pathology , Adipose Tissue, Brown/ultrastructure , Adipose Tissue, White/drug effects , Adipose Tissue, White/enzymology , Adipose Tissue, White/ultrastructure , Animals , Diet, High-Fat , Energy Metabolism/drug effects , Fatty Acid-Binding Proteins/metabolism , Gene Expression Regulation/drug effects , Homeostasis/drug effects , Humans , Insulin/pharmacology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mitochondria/metabolism , Mitochondria/ultrastructure , Organ Size/drug effects , Oxygen Consumption/drug effects , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Phenotype , Thinness/metabolism , Thinness/pathology , Trans-Activators/metabolism , Transcription Factors , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
The reparative reaction is considered to be important during the occurrence of collapse in the femoral head with osteonecrosis (ONFH), but little is known about the long-term reparative process. The aim of this study was to determine and analyze the altered microRNA expression profile in the reparative interface of ONFH, and further validate the expression of the involved genes in the predicted pathways. Microarray analysis was performed comparing the reparative interface of patients with ONFH and normal tissue of patients with fresh femoral neck fracture (FNF) and partly validated by real-time PCR. Potential target genes of differentially expressed miRNAs were predicted by TargetScan and miRanda, and the target genes were used for further bioinformatics analysis such as Gene Ontology and Pathway assay. The filtered miRNAs and genes in the predict pathways were further examined by real-time PCR in another 6 independent ONFH patients. Among the 2578 miRNAs identified, 17 were consistently differentially expressed, 12 of which are up-regulated and 5 down-regulated. GO classification showed that the predicted target genes of these miRNAs are involved in signal transduction, cell differentiation, methylation, cell growth and apoptosis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) classification indicated that these genes play a role in angiogenesis and Wnt signaling pathways. The expression of miR-34a and miR-146a and genes in the predict pathways were significantly up-regulated. This study presented a global view of miRNA expression in the reparative interface of osteonecrosis. In addition, our data provided novel and robust information for further researches in the pathogenesis and molecular events of ONFH.