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

Maria Kolak; Jukka Westerbacka; Vidya R. Velagapudi; Dick Wågsäter; Laxman Yetukuri; Janne Makkonen; Aila Rissanen; Anna-Maija Häkkinen; Monica Lindell; Robert Bergholm; Anders Hamsten; Per Eriksson; Rachel M. Fisher; Matej Orešic; Hannele Yki-Järvinen

Disclosures

Diabetes. 2007;56(8):1960-1968. 

In This Article

Abstract and Introduction

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.

Introduction

Recent studies have shown that the fatty liver is insulin resistant and overproduces many, if not most, of the cardiovascular risk factors associated with the metabolic syndrome.[1] Insulin resistance in the liver results in VLDL overproduction, which leads to hypertriglyceridemia and low HDL cholesterol levels.[2] The liver, once fatty, also overproduces fibrinogen, von Willebrand factor, C-reactive protein,[3] and plasminogen activator inhibitor (PAI)-1.[3,4] Resistance to insulin inhibition of hepatic glucose production basally and postprandially results in hyperglycemia and hyperinsulinemia.[1] Abdominal obesity is more common in individuals with a fatty liver than in those without, and intra-abdominal fat correlates with liver fat (LFAT).[5,6] However, the amount of fat in the liver is poorly correlated with subcutaneous obesity[1,5] and predicts the metabolic syndrome,[7] type 2 diabetes,[8,9] and cardiovascular disease[10] independent of obesity.

Factors regulating LFAT content independent of obesity are poorly understood. Previous studies have shown that adipose tissue in obese subjects is inflamed compared with nonobese subjects.[11,12] This inflammation is characterized by an increase in macrophage numbers and expression of macrophage markers such as CD68.[11,12] Expression of insulin-resistant genes and the local production of their protein products by macrophages in adipose tissue are also increased in obese compared with nonobese subjects.[13,14,15,16] These and other changes may contribute to increased lipolysis and adiponectin deficiency, which characterize adipose tissue of insulin-resistant subjects and may increase LFAT content.[17] The stimulus for macrophage accumulation in adipose tissue, on the other hand, is unclear. The first studies comparing obese and nonobese subjects showed macrophage accumulation to be directly related to cell size.[11] Recently, Cinti et al.[18] showed that in obese compared with nonobese subjects, macrophages surround dead adipocytes, and they suggested that adipocyte cell death could serve as one stimulus for macrophage infiltration.

Regarding the causes of adipose tissue inflammation, we have previously shown in two independent studies that the percentage of total fat in diet is positively correlated with LFAT content.[19,20] This could alter fatty acid composition of adipose tissue.[21] Recent advances in ultra-performance liquid chromatography combined with mass spectrometry methodology and data processing have enabled structural characterization and quantitation of hundreds of lipid species in minute biological samples.[22,23] Such methodology has hitherto not been used to study human adipose tissue.

In the present study, we reasoned that fat accumulation in the liver distinguishes between those obese subjects who develop insulin resistance and those who do not. We hypothesized if adipose tissue inflammation is important for fat accumulation in the liver, then adipose tissue should be inflamed in obese subjects who have excess fat in the liver compared with equally obese subjects with normal LFAT content. To examine this, we recruited a group of obese women with a narrow range of BMIs and measured their LFAT content using proton magnetic resonance spectroscopy and body composition using magnetic resonance imaging (MRI) and other techniques. The women were divided into groups with high and normal LFAT content, based on their median LFAT content. The groups were matched with respect to age and body weight. A surgical biopsy of subcutaneous adipose tissue was taken for immunohistochemistry and gene expression studies. Lipidomic analyses were performed using the ultra-performance liquid chromatography combined with mass spectrometry platform.

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