title: The role of adipose tissue asymmetric dimethylarginine/dimethylarginine dimethylaminohydrolase pathway in adipose tissue phenotype and metabolic abnormalities in subtotally nephrectomized rats.
abstract: BACKGROUND
  The lipodystrophy-like phenotype has been suggested in early chronic kidney disease (CKD). It includes adipose tissue atrophy, systemic insulin resistance (IR), dyslipidemia and ectopic lipid accumulation. To elucidate its pathogenesis, we investigated the role of two uremic toxins that affect insulin sensitivity: an endogenous nitric oxide synthase inhibitor, and asymmetric dimethylarginine (ADMA) and indoxyl sulfate (IS).
  
  
  METHODS
  Six-week-old Sprague-Dawley rats were rendered CKD by subtotal nephrectomy (Nx) and compared with sham-operated rats. Cultured 3T3-L1 fibroblasts were differentiated into mature adipocytes with or without ADMA. Transgenic (Tg) mice overexpressing each isoform of ADMA degrading enzyme, dimethylarginine dimethylaminohydrolase 1 (DDAH1) and DDAH2 were subject to Nx and their phenotypes were investigated.
  
  
  RESULTS
  In Nx rats, IR was evident and insulin stimulation failed to activate insulin signaling in adipose tissues. Adipose tissue weight, adipocyte size and adipocyte differentiation marker expressions decreased as a consequence of IR in Nx. Tissue lipid content in the liver and muscle increased in Nx rats. Tissue levels of ADMA, IS and oxidative stress increased in the adipose tissue of Nx rats. Both DDAH1 and DDAH2 expressions decreased, and a putative IS receptor, aryl hydrocarbon receptor, expression increased in the adipose tissue of Nx rats. ADMA inhibited adipocyte differentiation, triglyceride accumulation and insulin signaling, which were reversed by pretreatment with cGMP. In each type of Tg mice overexpressing DDAH1 or DDAH2, all lipodystrophy-like phenotypes induced by Nx were reversed.
  
  
  CONCLUSIONS
  In mild CKD, dysregulation of the ADMA/DDAH pathway in adipose tissue triggers lipodystrophy-like phenotype changes, including ectopic fat depositions.
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Minakuchi
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Wakino
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Kozi
authors.initials: K
authors.lastname: Hosoya
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Sueyasu
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shinozuka
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yoshifuji
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Futatsugi
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Motoaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanda
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Tokuyama
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000581:Amidohydrolases / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000235:genetics; D015153:Blotting, Western; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009392:Nephrectomy / Q000009:adverse effects; D018384:Oxidative Stress / Q000235:genetics*; D010641:Phenotype; D012313:RNA / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D012313:RNA; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase
keywords: ADMA; chronic kidney disease; indoxyl sulfate; insulin resistance; uremic toxins