title: Metformin ameliorates IL-6-induced hepatic insulin resistance via induction of orphan nuclear receptor small heterodimer partner (SHP) in mouse models.
abstract: OBJECTIVE
  IL-6 is a proinflammatory cytokine associated with the pathogenesis of hepatic diseases. Metformin is an anti-diabetic drug used for the treatment of type 2 diabetes, and orphan nuclear receptor small heterodimer partner (SHP, also known as NR0B2), a transcriptional co-repressor, plays an important role in maintaining metabolic homeostasis. Here, we demonstrate that metformin-mediated activation of AMP-activated protein kinase (AMPK) increases SHP protein production and regulates IL-6-induced hepatic insulin resistance.
  
  
  METHODS
  We investigated metformin-mediated SHP production improved insulin resistance through the regulation of an IL-6-dependent pathway (involving signal transducer and activator of transcription 3 [STAT3] and suppressor of cytokine signalling 3 [SOCS3]) in both Shp knockdown and Shp null mice.
  
  
  RESULTS
  IL-6-induced STAT3 transactivation and SOCS3 production were significantly repressed by metformin, adenoviral constitutively active AMPK (Ad-CA-AMPK), and adenoviral SHP (Ad-SHP), but not in Shp knockdown, or with the adenoviral dominant negative form of AMPK (Ad-DN-AMPK). Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and protein localisation studies showed that SHP inhibits DNA binding of STAT3 on the Socs3 gene promoter via interaction and colocalisation within the nucleus. Upregulation of inflammatory genes and downregulation of hepatic insulin signalling by acute IL-6 treatment were observed in wild-type mice but not in Shp null mice. Finally, chronic IL-6 exposure caused hepatic insulin resistance, leading to impaired insulin tolerance and elevated gluconeogenesis, and these phenomena were aggravated in Shp null mice.
  
  
  CONCLUSIONS
  Our results demonstrate that SHP upregulation by metformin may prevent hepatic disorders by regulating the IL-6-dependent pathway, and that this pathway can help to ameliorate the pathogenesis of cytokine-mediated metabolic dysfunction.
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Y D
authors.initials: YD
authors.lastname: Kim
authors.forename: Y H
authors.initials: YH
authors.lastname: Kim
authors.forename: Y M
authors.initials: YM
authors.lastname: Cho
authors.forename: D K
authors.initials: DK
authors.lastname: Kim
authors.forename: S W
authors.initials: SW
authors.lastname: Ahn
authors.forename: J M
authors.initials: JM
authors.lastname: Lee
authors.forename: D
authors.initials: D
authors.lastname: Chanda
authors.forename: M
authors.initials: M
authors.lastname: Shong
authors.forename: C H
authors.initials: CH
authors.lastname: Lee
authors.forename: H S
authors.initials: HS
authors.lastname: Choi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D015850:Interleukin-6; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C099713:nuclear receptor subfamily 0, group B, member 2; D008687:Metformin; D055372:AMP-Activated Protein Kinases