title: Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity.
abstract: OBJECTIVE
  We sought to determine whether adipose tissue is inflamed in individuals with increased liver fat (LFAT) independently of obesity.
  
  
  METHODS
  A total of 20 nondiabetic, healthy, obese women were divided into normal and high LFAT groups based on their median LFAT level (2.3 +/- 0.3 vs. 14.4 +/- 2.9%). Surgical subcutaneous adipose tissue biopsies were studied using quantitative PCR, immunohistochemistry, and a lipidomics approach to search for putative mediators of insulin resistance and inflammation. The groups were matched for age and BMI. The high LFAT group had increased insulin (P = 0.0025) and lower HDL cholesterol (P = 0.02) concentrations.
  
  
  RESULTS
  Expression levels of the macrophage marker CD68, the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator-activated receptor-gamma and adiponectin decreased in the high LFAT group. CD68 expression correlated with the number of macrophages and crown-like structures (multiple macrophages fused around dead adipocytes). Concentrations of 154 lipid species in adipose tissue revealed several differences between the groups, with the most striking being increased concentrations of triacylglycerols, particularly long chain, and ceramides, specifically Cer(d18:1/24:1) (P = 0.01), in the high LFAT group. Expression of sphingomyelinases SMPD1 and SMPD3 were also significantly increased in the high compared with normal LFAT group.
  
  
  CONCLUSIONS
  Adipose tissue is infiltrated with macrophages, and its content of long-chain triacylglycerols and ceramides is increased in subjects with increased LFAT compared with equally obese subjects with normal LFAT content. Ceramides or their metabolites could contribute to adverse effects of long-chain fatty acids on insulin resistance and inflammation.
authors.affiliation: Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Kolak
authors.forename: Jukka
authors.initials: J
authors.lastname: Westerbacka
authors.forename: Vidya R
authors.initials: VR
authors.lastname: Velagapudi
authors.forename: Dick
authors.initials: D
authors.lastname: Wågsäter
authors.forename: Laxman
authors.initials: L
authors.lastname: Yetukuri
authors.forename: Janne
authors.initials: J
authors.lastname: Makkonen
authors.forename: Aila
authors.initials: A
authors.lastname: Rissanen
authors.forename: Anna-Maija
authors.initials: AM
authors.lastname: Häkkinen
authors.forename: Monica
authors.initials: M
authors.lastname: Lindell
authors.forename: Robert
authors.initials: R
authors.lastname: Bergholm
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Fisher
authors.forename: Matej
authors.initials: M
authors.lastname: Oresic
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D001772:Blood Cell Count; D048429:Cell Size; D002518:Ceramides / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D016207:Cytokines / Q000235:genetics; D005215:Fasting; D005234:Fatty Liver / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006262:Health; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000097:blood; D008264:Macrophages / Q000166:cytology; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D014280:Triglycerides / Q000097:blood; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002518:Ceramides; D008076:Cholesterol, HDL; D016207:Cytokines; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D014280:Triglycerides; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C051321:SERPINE1 protein, human