title: The dual function of hepatic SOCS3 in insulin resistance in vivo.
abstract: Inflammation associates with insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. The suppressor of cytokine signaling 3 (SOCS3), which is induced by pro-inflammatory cytokines, such as TNFalpha and IL-6, has been implicated in inflammation-mediated insulin resistance in the liver and adipocytes. However, no genetic evidence has been provided for the involvement of SOCS3 on insulin resistance. Here, we generated hepatocyte-specific SOCS3-deficient (L-SOCS3 cKO) mice and examined insulin sensitivity. Being consistent with a previous idea, the loss of SOCS3 in the liver apparently improved insulin sensitivity. However, unexpectedly, L-SOCS3 cKO mice exhibited obesity and systemic insulin resistance with age. Insulin signaling was rather suppressed in muscles, suggesting that deletion of the SOCS3 gene in the liver modulates insulin sensitivity in other organs. Anti-inflammatory reagent, sodium salicylate, partial improved insulin resistance of aged L-SOCS3 cKO mice, suggesting that enhanced inflammatory status is associated with the phenotype of these mice. STAT3 was hyperactivated and acute-phase proteins were elevated in L-SOCS3 cKO mice liver, which were reduced by sodium salicylate treatment. We conclude that hepatic SOCS3 is a mediator of insulin resistance in the liver; however, lack of SOCS3 in the liver promotes systemic insulin resistance by mimicking chronic inflammation.
authors.affiliation: Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, University of Kyushu, Maidashi 3-1-1, Fukuoka 812-8582, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Torisu
authors.forename: Naoichi
authors.initials: N
authors.lastname: Sato
authors.forename: Daigo
authors.initials: D
authors.lastname: Yoshiga
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mori
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Iida
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics; D015870:Gene Expression; D007249:Inflammation / Q000235:genetics; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins