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ADIPOSE TISSUE INFLAMMATION AND INCREASED CERAMIDE CONTENT CHARACTERIZE SUBJECTS WITH HIGH LIVER FAT CONTENT INDEPENDENT OF OBESITY

Maria Kolak¹, Jukka Westerbacka², Vidya R. Velagapudi³, Dick Wågsäter¹, Laxman Yetukuri³, Janne Makkonen^2,,4, Aila Rissanen⁵, Anna-Maija Häkkinen⁶, Monica Lindell¹, Robert Bergholm^2,,4, Anders Hamsten¹, Per Eriksson¹, Rachel M. Fisher¹, Matej Orei³, and Hannele Yki-Järvinen^1,,2

¹Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
²University of Helsinki, Department of Medicine, Division of Diabetes, Helsinki, Finland
³VTT Technical Research Centre of Finland, Espoo, Finland
⁴Minerva Medical Research Institute, Helsinki, Finland
⁵University of Helsinki, Obesity Research Unit, Helsinki, Finland
⁶University of Helsinki, Department of Oncology, Helsinki, Finland

Correspondence: ykijarvi{at}cc.helsinki.fi

Key Words: insulin • PPAR • MCP-1 • ceramides • lipidomics

Objective:To determine whether whether adipose tissue is inflamed in individuals with increased liver fat independent of obesity.

Research Design and Methods:20 non-diabetic healthy obese women were divided into normal and high liver fat (LFAT) groups based on their median LFAT (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 body mass index. The high LFAT group had increased insulin (p=0.0025) and lower HDL cholesterol (p=0.02) concentrations.

Results:Expression of the macrophage marker CD68, the chemokines MCP-1 and MIP-1, and PAI-1 were significantly increased and those of PPAR 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, 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 as compared to 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 to 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.

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