Adipose Tissue Inflammation and Increased Ceramide Content Characterize Subjects With High Liver Fat Content Independent of Obesity

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 8; pp. 1960 - 1968
• Main Authors: Kolak, Maria, Westerbacka, Jukka, Velagapudi, Vidya R., Wågsäter, Dick, Yetukuri, Laxman, Makkonen, Janne, Rissanen, Aila, Häkkinen, Anna-Maija, Lindell, Monica, Bergholm, Robert, Hamsten, Anders, Eriksson, Per, Fisher, Rachel M., Orešic̆, Matej, Yki-Järvinen, Hannele
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.08.2007
• Subjects: Abdomen; Adipocytes; Adipose tissue; Adipose Tissue - cytology; Adipose Tissue - metabolism; Adipose tissues; Adolescent; Adult; Antigens, CD - genetics; Antigens, Differentiation, Myelomonocytic - genetics; Biological and medical sciences; Biopsy; Blood Cell Count; Body composition; Body fat; Cell Size; Ceramides - metabolism; Cholesterol; Cholesterol, HDL - blood; Chromatography; Complications and side effects; Cytokines - genetics; Diabetes; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fasting; Fat; Fats; Fatty Liver - complications; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - pathology; Female; Gene expression; Gene Expression Regulation; Glucose; Health; Health aspects; High density lipoprotein; Humans; Immunohistochemistry; Inflammation; Inflammation - complications; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Insulin - blood; Insulin resistance; Liver; Macrophages - cytology; Magnetic resonance imaging; Mass spectrometry; Medical sciences; Metabolic diseases; Metabolic syndrome; Metabolites; Middle Aged; Obesity; Obesity - genetics; Obesity - metabolism; Obesity - pathology; Physiological aspects; Plasminogen Activator Inhibitor 1 - genetics; Proteins; Research design; RNA, Messenger - genetics; Scientific imaging; Triglycerides - blood; Womens health; Sweden; Finland; Endocrinopathy; Human; Obesity; Adipose tissue; Digestive system; Diabetes mellitus; Liver; Nutrition disorder; Sphingolipid; Ceramide; Inflammation; Nutritional status
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db07-0111

Adipose Tissue Inflammation and Increased Ceramide Content Characterize Subjects With High Liver Fat Content Independent of Obesity Maria Kolak 1 , Jukka Westerbacka 2 , Vidya R. Velagapudi 3 , Dick Wågsäter 1 , Laxman Yetukuri 3 , Janne Makkonen 2 4 , Aila Rissanen 5 , Anna-Maija Häkkinen 6 , Monica Lindell 1 , Robert Bergholm 2 4 , Anders Hamsten 1 , Per Eriksson 1 , Rachel M. Fisher 1 , Matej Orešic̆ 3 and Hannele Yki-Järvinen 1 2 1 Atherosclerosis Research Unit, Department of Medicine, King Gustaf V. Research Institute, Karolinska Institutet, Stockholm, Sweden 2 Division of Diabetes, Department of Medicine, University of Helsinki, Helsinki, Finland 3 VTT Technical Research Centre of Finland, Espoo, Finland 4 Minerva Medical Research Institute, Helsinki, Finland 5 Obesity Research Unit, University of Helsinki, Helsinki, Finland 6 Department of Oncology, University of Helsinki, Helsinki, Finland Address correspondence and reprint requests to Hannele Yki-Järvinen, MD, P.O. Box 700, Room C426B, Biomedicum, Haartmaninkatu 8, 00029 HUS, Helsinki, Finland. E-mail: ykijarvi{at}cc.helsinki.fi Abstract OBJECTIVE— We sought to determine whether adipose tissue is inflamed in individuals with increased liver fat (LFAT) independently of obesity. RESEARCH DESIGN AND 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-1α, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator–activated receptor-γ 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. LFAT, liver fat MCP-1, monocyte chemoattractant protein-1 MIP-1α, macrophage inflammatory protein-1α PAI, plasminogen activator inhibitor PPAR, proliferator–activated receptor TNF-α, tumor necrosis factor-α Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 9 July 2007. DOI: 10.2337/db07-0111. M.K. and J.W. contributed equally to this work. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0111 . This work is part of the project Hepatic and Adipose Tissue and Functions in the Metabolic Syndrome (HEPADIP) ( http://www.hepadip.org/ ), which is supported by the European Commission as an integrated project under the 6th Framework Programme (contract LSHM-CT-2005-018734). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 9, 2007. Received January 25, 2007. DIABETES