title: Tribbles 3 inhibits brown adipocyte differentiation and function by suppressing insulin signaling.
abstract: Recent studies have demonstrated that adult humans have substantial amounts of functioning brown adipose tissue (BAT). Since BAT has been implicated as an anti-obese and anti-diabetic tissue, it is important to understand the signaling molecules that regulate BAT function. There has been a link between insulin signaling and BAT metabolism as deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function. Tribbles 3 (TRB3) is a pseudo kinase that has been shown to regulate metabolism and insulin signaling in multiple tissues but the role of TRB3 in BAT has not been studied. In this study, we found that TRB3 expression was present in BAT and overexpression of TRB3 in brown preadipocytes impaired differentiation and decreased expression of BAT markers. Furthermore, TRB3 overexpression resulted in significantly lower oxygen consumption rates for basal and proton leakage, indicating decreased BAT activity. Based on previous studies showing that deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function, we assessed insulin signaling in brown preadipocytes and BAT in vivo. Overexpression of TRB3 in cells impaired insulin-stimulated IRS1 and Akt phosphorylation, whereas TRB3KO mice displayed improved IRS1 and Akt phosphorylation. Finally, deletion of IRS1 abolished the function of TRB3 to regulate BAT differentiation and metabolism. These data demonstrate that TRB3 inhibits insulin signaling in BAT, resulting in impaired differentiation and function.
authors.affiliation: Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Ha-Won
authors.initials: HW
authors.lastname: Jeong
authors.affiliation: Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Ran Hee
authors.initials: RH
authors.lastname: Choi
authors.affiliation: Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: McClellan
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Piroli
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
authors.forename: Norma
authors.initials: N
authors.lastname: Frizzell
authors.affiliation: Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Tseng
authors.affiliation: Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Goodyear
authors.affiliation: Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208, USA. Electronic address: kohh@mailbox.sc.edu.
authors.forename: Ho-Jin
authors.initials: HJ
authors.lastname: Koh
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology* / Q000378:metabolism*; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation; D007328:Insulin / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D007328:Insulin; C474830:TRB3 protein, mouse
keywords: Brown adipose tissue; Insulin signaling; UCP1