title: Kinase Inactive Tyrosine Kinase (Tyk2) Supports Differentiation of Brown Fat Cells.
abstract: It has been known for decades that brown adipose tissue (BAT) plays a central role in maintaining body temperature in hibernating animals and human infants. Recently, it has become evident that there are also depots of brown fat in adult humans, and the mass of brown fat is inversely correlated with body weight. There are a variety of transcription factors implicated in the differentiation of classical Myf5+ brown preadipocytes, one of the most important of which is PRDM16. We have recently identified that in addition to PRDM16, the tyrosine kinase Tyk2 and the STAT3 transcription factor are required for the differentiation of Myf5 positive brown preadipocytes both in cell culture and in mice. Tyk2 is a member of the Jak family of tyrosine kinases, which are activated by exposure of cells to different cytokines and growth factors. In this study we report the surprising observation that a mutated form of Tyk2, which lacks tyrosine kinase activity (Tyk2KD) restores differentiation of brown preadipocytes in vitro as well as in Tyk2-/- mice. Furthermore, expression of the Tyk2KD transgene in brown fat reverses the obese phenotype of Tyk2-/- animals. Treatment of cells with Jak-selective inhibitors suggests that the mechanism by which Tyk2KD functions to restore BAT differentiation is by dimerizing with kinase active Jak1 or Jak2. These results indicate that there are redundant mechanisms by which members of the Jak family can contribute to differentiation of BAT.
authors: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298.
authors: Vidisha
authors: V
authors: Raje
authors: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298.
authors: Marta
authors: M
authors: Derecka
authors: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298.
authors: Marc
authors: M
authors: Cantwell
authors: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298.
authors: Jeremy
authors: J
authors: Meier
authors: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298.|Medical Service, McGuire Department of Veterans Affairs Medical Center, Richmond, Virginia 23249.
authors: Karol
authors: K
authors: Szczepanek
authors: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298.
authors: Jennifer D
authors: JD
authors: Sisler
authors: Institute of Animal Breeding and Genetics, School of Veterinary Medicine, University of Vienna, A-1210, Vienna, Austria.
authors: Birgit
authors: B
authors: Strobl
authors: Department of Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140; and.
authors: Ana
authors: A
authors: Gamero
authors: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908.
authors: Thurl E
authors: TE
authors: Harris
authors: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298.
authors: Andrew C
authors: AC
authors: Larner
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology*; D050156:Adipogenesis; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D051787:Myogenic Regulatory Factor 5; D009570:Nitriles; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D011720:Pyrazoles; D011743:Pyrimidines; D053634:TYK2 Kinase / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C497418:Myf5 protein, mouse; D051787:Myogenic Regulatory Factor 5; D009570:Nitriles; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C521133:Prdm16 protein, mouse; D011720:Pyrazoles; D011743:Pyrimidines; D014157:Transcription Factors; C540383:ruxolitinib; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse