Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity.
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.
Kolak
Maria
M
Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden.
Westerbacka
Jukka
J
Velagapudi
Vidya R
VR
Wågsäter
Dick
D
Yetukuri
Laxman
L
Makkonen
Janne
J
Rissanen
Aila
A
Häkkinen
Anna-Maija
AM
Lindell
Monica
M
Bergholm
Robert
R
Hamsten
Anders
A
Eriksson
Per
P
Fisher
Rachel M
RM
Oresic
Matej
M
Yki-Järvinen
Hannele
H
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
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