title: A novel therapeutic approach to treating obesity through modulation of TGFβ signaling.
abstract: Obesity results from disproportionately high energy intake relative to energy expenditure. Many therapeutic strategies have focused on the intake side of the equation, including pharmaceutical targeting of appetite and digestion. An alternative approach is to increase energy expenditure through physical activity or adaptive thermogenesis. A pharmacological way to increase muscle mass and hence exercise capacity is through inhibition of the activin receptor type IIB (ActRIIB). Muscle mass and strength is regulated, at least in part, by growth factors that signal via ActRIIB. Administration of a soluble ActRIIB protein comprised of a form of the extracellular domain of ActRIIB fused to a human Fc (ActRIIB-Fc) results in a substantial muscle mass increase in normal mice. However, ActRIIB is also present on and mediates the action of growth factors in adipose tissue, although the function of this system is poorly understood. In the current study, we report the effect of ActRIIB-Fc to suppress diet-induced obesity and linked metabolic dysfunctions in mice fed a high-fat diet. ActRIIB-Fc induced a brown fat-like thermogenic gene program in epididymal white fat, as shown by robustly increased expression of the thermogenic genes uncoupling protein 1 and peroxisomal proliferator-activated receptor-γ coactivator 1α. Finally, we identified multiple ligands capable of reducing thermogenesis that represent likely target ligands for the ActRIIB-Fc effects on the white fat depots. These data demonstrate that novel therapeutic ActRIIB-Fc improves obesity and obesity-linked metabolic disease by both increasing skeletal muscle mass and by inducing a gene program of thermogenesis in the white adipose tissues.
authors.affiliation: Acceleron Pharma, Inc. Preclinical Pharmacology, Cambridge, Massachusetts 02139, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Koncarevic
authors.forename: Shingo
authors.initials: S
authors.lastname: Kajimura
authors.forename: Milton
authors.initials: M
authors.lastname: Cornwall-Brady
authors.forename: Amy
authors.initials: A
authors.lastname: Andreucci
authors.forename: Abigail
authors.initials: A
authors.lastname: Pullen
authors.forename: Dianne
authors.initials: D
authors.lastname: Sako
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kumar
authors.forename: Asya V
authors.initials: AV
authors.lastname: Grinberg
authors.forename: Katia
authors.initials: K
authors.lastname: Liharska
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Ucran
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Howard
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
authors.forename: Jasbir
authors.initials: J
authors.lastname: Seehra
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lachey
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism*; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000166:cytology; D009765:Obesity / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors; D020349:Surface Plasmon Resonance; D022722:Thermogenesis; D014057:Tomography, X-Ray Computed / Q000379:methods; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D008024:Ligands; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B