title: Selective modulation of Wnt ligands and their receptors in adipose tissue by chronic hyperadiponectinemia.
abstract: BACKGROUND
  Adiponectin-transgenic mice had many small adipocytes in both subcutaneous and visceral adipose tissues, and showed higher sensitivity to insulin, longer life span, and reduced chronic inflammation. We hypothesized that adiponectin regulates Wnt signaling in adipocytes and thereby modulates adipocyte proliferation and chronic inflammation in adipose tissue.
  
  
  METHODS
  We examined the expression of all Wnt ligands and their receptors and the activity of Wnt signaling pathways in visceral adipose tissue from wild-type mice and two lines of adiponectin-transgenic mice. The effects of adiponectin were also investigated in cultured 3T3-L1 cells.
  
  
  RESULTS
  The Wnt5b, Wnt6, Frizzled 6 (Fzd6), and Fzd9 genes were up-regulated in both lines of transgenic mice, whereas Wnt1, Wnt2, Wnt5a, Wnt9b, Wnt10b, Wnt11, Fzd1, Fzd2, Fzd4, Fzd7, and the Fzd coreceptor low-density-lipoprotein receptor-related protein 6 (Lrp6) were reduced. There was no difference in total β-catenin levels in whole-cell extracts, non-phospho-β-catenin levels in nuclear extracts, or mRNA levels of β-catenin target genes, indicating that hyperadiponectinemia did not affect canonical Wnt signaling. In contrast, phosphorylated calcium/calmodulin-dependent kinase II (p-CaMKII) and phosphorylated Jun N-terminal kinase (p-JNK) were markedly reduced in adipose tissue from the transgenic mice. The adipose tissue of the transgenic mice consisted of many small cells and had increased expression of adiponectin, whereas cyclooxygenase-2 expression was reduced. Wnt5b expression was elevated in preadipocytes of the transgenic mice and decreased in diet-induced obese mice, suggesting a role in adipocyte differentiation. Some Wnt genes, Fzd genes, and p-CaMKII protein were down-regulated in 3T3-L1 cells cultured with a high concentration of adiponectin.
  
  
  CONCLUSIONS
  Chronic hyperadiponectinemia selectively modulated the expression of Wnt ligands, Fzd receptors and LRP coreceptors accompanied by the inhibition of the Wnt/Ca(2+) and JNK signaling pathways, which may be involved in the altered adipocyte cellularity, endogenous adiponectin production, and anti-inflammatory action induced by hyperadiponectinemia.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Wada
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hashinaga
authors.forename: Shuichi
authors.initials: S
authors.lastname: Otabe
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yuan
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Kurita
authors.forename: Satomi
authors.initials: S
authors.lastname: Kakino
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ohoki
authors.forename: Hitomi
authors.initials: H
authors.lastname: Nakayama
authors.forename: Tomoka
authors.initials: T
authors.lastname: Fukutani
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tajiri
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yamada
mesh_terms: D041721:3T3-L1 Cells; D052242:Adiponectin / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D051157:Frizzled Receptors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018110:Receptors, Lipoprotein / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D052242:Adiponectin; D051157:Frizzled Receptors; D008024:Ligands; D018110:Receptors, Lipoprotein; D051153:Wnt Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2