title: Blockade of the activin receptor IIb activates functional brown adipogenesis and thermogenesis by inducing mitochondrial oxidative metabolism.
abstract: Brown adipose tissue (BAT) is a key tissue for energy expenditure via fat and glucose oxidation for thermogenesis. In this study, we demonstrate that the myostatin/activin receptor IIB (ActRIIB) pathway, which serves as an important negative regulator of muscle growth, is also a negative regulator of brown adipocyte differentiation. In parallel to the anticipated hypertrophy of skeletal muscle, the pharmacological inhibition of ActRIIB in mice, using a neutralizing antibody, increases the amount of BAT without directly affecting white adipose tissue. Mechanistically, inhibition of ActRIIB inhibits Smad3 signaling and activates the expression of myoglobin and PGC-1 coregulators in brown adipocytes. Consequently, ActRIIB blockade in brown adipose tissue enhances mitochondrial function and uncoupled respiration, translating into beneficial functional consequences, including enhanced cold tolerance and increased energy expenditure. Importantly, ActRIIB inhibition enhanced energy expenditure only at ambient temperature or in the cold and not at thermoneutrality, where nonshivering thermogenesis is minimal, strongly suggesting that brown fat activation plays a prominent role in the metabolic actions of ActRIIB inhibition.
authors.affiliation: MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Fournier
authors.forename: Ben
authors.initials: B
authors.lastname: Murray
authors.forename: Sabine
authors.initials: S
authors.lastname: Gutzwiller
authors.forename: Stefan
authors.initials: S
authors.lastname: Marcaletti
authors.forename: David
authors.initials: D
authors.lastname: Marcellin
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bergling
authors.forename: Sophie
authors.initials: S
authors.lastname: Brachat
authors.forename: Elke
authors.initials: E
authors.lastname: Persohn
authors.forename: Eliane
authors.initials: E
authors.lastname: Pierrel
authors.forename: Florian
authors.initials: F
authors.lastname: Bombard
authors.forename: Shinji
authors.initials: S
authors.lastname: Hatakeyama
authors.forename: Anne-Ulrike
authors.initials: AU
authors.lastname: Trendelenburg
authors.forename: Frederic
authors.initials: F
authors.lastname: Morvan
authors.forename: Brian
authors.initials: B
authors.lastname: Richardson
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
authors.forename: Estelle
authors.initials: E
authors.lastname: Lach-Trifilieff
authors.forename: Jerome N
authors.initials: JN
authors.lastname: Feige
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D052437:Adipocytes, Brown / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000502:physiology*; D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D057134:Antibodies, Neutralizing; D002454:Cell Differentiation; D004734:Energy Metabolism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D055435:Myostatin / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D022722:Thermogenesis / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; C525912:Mstn protein, mouse; D055435:Myostatin; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B