title: Pioglitazone upregulates adiponectin receptor 2 in 3T3-L1 adipocytes.
abstract: OBJECTIVE
  Pioglitazone, a full peroxisome proliferator-activated receptor (PPAR)-γ agonist, improves insulin sensitivity by increasing circulating adiponectin levels. However, the molecular mechanisms by which pioglitazone induces insulin sensitization are not fully understood. In this study, we investigated whether pioglitazone improves insulin resistance via upregulation of either 2 distinct receptors for adiponectin (AdipoR1 or AdipoR2) expression in 3T3-L1 adipocytes.
  
  
  METHODS
  Glucose uptake was evaluated by 2-[(3)H] deoxy-glucose uptake assay in 3T3-L1 adipocytes with pioglitazone treatment. AdipoR1 and AdipoR2 mRNA expressions were analyzed by qRT-PCR.
  
  
  RESULTS
  We first confirmed that pioglitazone significantly increased insulin-induced 2-deoxyglucose (2-DOG) uptake in 3T3-L1 adipocytes. Next, we investigated the mRNA expression and regulation of AdipoR1 and AdipoR2 after treatment with pioglitazone. Interestingly, pioglitazone significantly induced AdipoR2 expression but it did not affect AdipoR1 expression. In addition, adenovirus-mediated PPARγ expression significantly enhanced the effects of pioglitazone on insulin-stimulated 2-DOG uptake and AdipoR2 expression in 3T3-L1 adipocytes. These data suggest that pioglitazone enhances adiponectin's autocrine and paracrine actions in 3T3-L1 adipocytes via upregulation of PPARγ-mediated AdipoR2 expression. Furthermore, we found that pioglitazone significantly increased AMP-activated protein kinase (AMPK) phosphorylation in insulin-stimulated 3T3-L1 adipocytes, but it did not lead to the phosphorylation of IRS-1, Akt, or protein kinase Cλ/ζ.
  
  
  CONCLUSIONS
  Our results suggest that pioglitazone increases insulin sensitivity, at least partly, by PPARγ-AdipoR2-mediated AMPK phosphorylation in 3T3-L1 adipocytes. In conclusion, the upregulation of AdipoR2 expression may be one of the mechanisms by which pioglitazone improves insulin resistance in 3T3-L1 adipocytes.
authors.affiliation: Department of Nephrology, Hypertension, Diabetology, Endocrinology, and Metabolism, Fukushima Medical University, 1Hikarigaoka, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kudoh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Satoh
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirai
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000187:drug effects; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D003847:Deoxyglucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000008:administration & dosage; D007333:Insulin Resistance; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000187:drug effects* / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D012333:RNA, Messenger; D054419:Receptors, Adiponectin; D045162:Thiazolidinediones; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; D003847:Deoxyglucose; D055372:AMP-Activated Protein Kinases; D000077205:Pioglitazone