title: Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue.
abstract: Insulin signaling plays a unique role in the regulation of energy homeostasis and the impairment of insulin action is associated with altered lipid metabolism, obesity, and Type 2 Diabetes. The main aim of this study was to provide further insight into the regulatory mechanisms governing the insulin signaling pathway by investigating the role of non-proteolytic ubiquitination in insulin-mediated activation of AKT.
  
  
  
  The molecular mechanism of AKT regulation through ubiquitination is first dissectedin vitroin 3T3-L1 preadipocytes and then validatedin vivousing mice with adipo-specific deletion of GPS2, an endogenous inhibitor of Ubc13 activity (GPS2-AKO mice).
  
  
  
  Our results indicate that K63 ubiquitination is a critical component of AKT activation in the insulin signaling pathway and that counter-regulation of this step is provided by GPS2 preventing AKT ubiquitination through inhibition of Ubc13 enzymatic activity. Removal of this negative checkpoint, through GPS2 downregulation or genetic deletion, results in sustained activation of insulin signaling bothin vitroandin vivo. As a result, the balance between lipid accumulation and utilization is shifted toward storage in the adipose tissue and GPS2-AKO mice become obese under normal laboratory chow diet. However, the adipose tissue of GPS2-AKO mice is not inflamed, the levels of circulating adiponectin are elevated, and systemic insulin sensitivity is overall improved.
  
  
  
  Our findings characterize a novel layer of regulation of the insulin signaling pathway based on non-proteolytic ubiquitination of AKT and define GPS2 as a previously unrecognized component of the insulin signaling cascade. In accordance with this role, we have shown that GPS2 presence in adipocytes modulates systemic metabolism by restricting the activation of insulin signaling during the fasted state, whereas in absence of GPS2, the adipose tissue is more efficient at lipid storage, and obesity becomes uncoupled from inflammation and insulin resistance.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA.
authors.forename: Carly T
authors.initials: CT
authors.lastname: Cederquist
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lentucci
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation St, Worcester, MA 01605, USA.
authors.forename: Camila
authors.initials: C
authors.lastname: Martinez-Calejman
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hayashi
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Orofino
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation St, Worcester, MA 01605, USA.
authors.forename: David
authors.initials: D
authors.lastname: Guertin
authors.affiliation: Diabetes Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, 1 Gustav Levy Place, New York, NY 10029, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Fried
authors.affiliation: Department of Medicine, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA.
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA.
authors.forename: M Dafne
authors.initials: MD
authors.lastname: Cardamone
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 72 E. Concord St, Boston, MA 02118, USA. Electronic address: vperissi@bu.edu.
authors.forename: Valentina
authors.initials: V
authors.lastname: Perissi
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D007249:Inflammation / Q000235:genetics; D007328:Insulin / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007333:Insulin Resistance / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009765:Obesity / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C572597:GPS2 protein, mouse; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C514982:Ube2n protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; Adipose tissue; GPS2; Insulin; Obesity; Ubiquitin