title: Inhibition of ERK1/2 pathway suppresses adiponectin secretion via accelerating protein degradation by Ubiquitin-proteasome system: relevance to obesity-related adiponectin decline.
abstract: OBJECTIVE
  Predominantly secreted by adipose tissue, adiponectin possesses insulin-sensitizing, anti-atherogenic, anti-inflammatory, and anti-angiogenic properties. Paradoxically, obesity is associated with declined plasma adiponectin levels; however, the underlying mechanisms remain elusive. In this study, we investigated the mechanistic involvement of MEK/ERK1/2 pathway in obesity-related adiponectin decrease.
  
  
  METHODS
  C57 BL/6 mice exposed to a high-fat diet (HFD) were employed as animal obesity model. Both fully-differentiated 3T3-L1 and mouse primary adipocytes were used in the in vitro experiments.
  
  
  RESULTS
  Obesity and plasma adiponectin decline induced by prolonged HFD exposure were associated with suppressed ERK1/2 activation in adipose tissue. In adipocytes, specific inhibition of MEK/ERK1/2 pathway decreased intracellular and secretory adiponectin levels, whereas adiponectin gene expression was increased, suggesting that MEK/ERK1/2 inhibition may promote adiponectin protein degradation. Cycloheximide (CHX)-chase assay revealed that MEK/ERK1/2 inhibition accelerated adiponectin protein degradation, which was prevented by MG132, a potent proteasome inhibitor. Immunoprecipitation assay showed that intracellular MEK/ERK1/2 activity was negatively associated with ubiquitinated adiponectin protein levels. Consistently, long-term HFD feeing in mice increased ubiquitinated adiponectin levels in the epididymal fat pads.
  
  
  CONCLUSIONS
  Adipose tissue MEK/ERK1/2 activity can differentially regulate adiponectin gene expression and protein abundance and its suppression in obesity may play a mechanistic role in obesity-related plasma adiponectin decline.
authors.affiliation: Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Gu
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Wang
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Dou
authors.forename: Ximei
authors.initials: X
authors.lastname: Zhang
authors.forename: Songtao
authors.initials: S
authors.lastname: Li
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Vu
authors.forename: Tong
authors.initials: T
authors.lastname: Yao
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Song
mesh_terms: D016475:3T3 Cells; D052242:Adiponectin / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D004797:Enzyme-Linked Immunosorbent Assay; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism; D047468:Immunoprecipitation; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009765:Obesity / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000502:physiology; D047495:PPAR gamma / Q000494:pharmacology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D052242:Adiponectin; D047495:PPAR gamma; D025801:Ubiquitin; D051058:Oncogene Protein v-akt; D046988:Proteasome Endopeptidase Complex
keywords: Adiponectin; ERK1/2; HFD; High-fat diet; I PPAR-γ; Obesity; PPAR-γ; TNF-α; UPS; Ubiquitin; Ubiquitin–proteasome system; extracellular signal-regulated kinases 1 and 2; peroxisome proliferator-activated receptor gamma; tumor necrosis factor-alpha