title: Brown fat determination and development from muscle precursor cells by novel action of bone morphogenetic protein 6.
abstract: Brown adipose tissue (BAT) plays a pivotal role in promoting energy expenditure by the virtue of uncoupling protein-1 (UCP-1) that differentiates BAT from its energy storing white adipose tissue (WAT) counterpart. The clinical implication of "classical" BAT (originates from Myf5 positive myoblastic lineage) or the "beige" fat (originates through trans-differentiation of WAT) activation in improving metabolic parameters is now becoming apparent. However, the inducers and endogenous molecular determinants that govern the lineage commitment and differentiation of classical BAT remain obscure. We report here that in the absence of any forced gene expression, stimulation with bone morphogenetic protein 6 (BMP6) induces brown fat differentiation from skeletal muscle precursor cells of murine and human origins. Through a comprehensive transcriptional profiling approach, we have discovered that two days of BMP6 stimulation in C2C12 myoblast cells is sufficient to induce genes characteristic of brown preadipocytes. This developmental switch is modulated in part by newly identified regulators, Optineurin (Optn) and Cyclooxygenase-2 (Cox2). Furthermore, pathway analyses using the Causal Reasoning Engine (CRE) identified additional potential causal drivers of this BMP6 induced commitment switch. Subsequent analyses to decipher key pathway that facilitates terminal differentiation of these BMP6 primed cells identified a key role for Insulin Like Growth Factor-1 Receptor (IGF-1R). Collectively these data highlight a therapeutically innovative role for BMP6 by providing a means to enhance the amount of myogenic lineage derived brown fat.
authors.affiliation: Centers for Therapeutic Innovation, Pfizer Inc., Boston, Massachusetts, United States of America.
authors.forename: Ankur
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Centers for Therapeutic Innovation, Pfizer Inc., Boston, Massachusetts, United States of America.
authors.forename: Christine
authors.initials: C
authors.lastname: Huard
authors.affiliation: CVMED, Pfizer Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Cecile
authors.initials: C
authors.lastname: Vernochet
authors.affiliation: Computational Sciences Center of Emphasis, Pfizer Inc, Cambridge, Massachusetts, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ziemek
authors.affiliation: Centers for Therapeutic Innovation, Pfizer Inc., Boston, Massachusetts, United States of America.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Knowlton
authors.affiliation: Centers for Therapeutic Innovation, Pfizer Inc., Boston, Massachusetts, United States of America.
authors.forename: Edyta
authors.initials: E
authors.lastname: Tyminski
authors.affiliation: BioTherapeutics Clinical Research, Pfizer Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Theresa
authors.initials: T
authors.lastname: Paradis
authors.affiliation: BioTherapeutics Clinical Research, Pfizer Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: CVMED, Pfizer Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Jessica E C
authors.initials: JE
authors.lastname: Jones
authors.affiliation: BioTherapeutics Clinical Research, Pfizer Inc., Cambridge, Massachusetts, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: von Schack
authors.affiliation: Global BioTherapeutics Technologies, Pfizer Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Brown
authors.affiliation: Centers for Therapeutic Innovation, Pfizer Inc., Boston, Massachusetts, United States of America.
authors.forename: Patrice M
authors.initials: PM
authors.lastname: Milos
authors.affiliation: Centers for Therapeutic Innovation, Pfizer Inc., Boston, Massachusetts, United States of America.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.affiliation: Centers for Therapeutic Innovation, Pfizer Inc., Boston, Massachusetts, United States of America.
authors.forename: Frederic
authors.initials: F
authors.lastname: Tremblay
authors.affiliation: Centers for Therapeutic Innovation, Pfizer Inc., Boston, Massachusetts, United States of America.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Martinez
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism*; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D016000:Cluster Analysis; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D017526:Receptor, IGF Type 1; D015398:Signal Transduction; D035582:Transcription Factor TFIIIA / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D018797:Cell Cycle Proteins; D005227:Fatty Acids; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; C409460:OPTN protein, human; D035582:Transcription Factor TFIIIA; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D051546:Cyclooxygenase 2; D017526:Receptor, IGF Type 1