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. 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 Ϯ 0.3 vs. 14.4 Ϯ 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 ϭ 0.0025) and lower HDL cholesterol (P ϭ 0.02) concentrations.RESULTS-Expression levels of the macrophage marker CD68, the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1␣, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator-activated receptor-␥ 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 ϭ 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.

Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?

“…The amount of liver fat is proportional to the number of features of the metabolic syndrome and is closely correlated with serum liver enzyme levels [7], which are subject to large inter-individual variability. On average, patients with NAFLD are more likely to have excess intraabdominal visceral fat and inflammatory changes in adipose tissue [8]; fat accumulation in the liver rather than in skeletal muscle is associated with features of the metabolic syndrome [9].…”

“…Parallel to changes in metabolic substrates, chronic inflammation is causally involved in insulin resistance and the metabolic syndrome, as mainly demonstrated by mechanistic studies in animal models [52]. Ectopic fat deposition in visceral adipose depots, heart and other depots increases the expression of several pro-inflammatory mediators such as monocyte chemotactic protein-1 and IL-6, leading to local macrophage infiltration and associated systemic chronic inflammation [8,44,45,53,54]. Specifically, recent human data suggest that abdominal obesity is associated with increased levels of circulating IL-6 [53,54].…”

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

“…AT inflammation is characterised by macrophage infiltration and increased levels of proinflammatory chemokines, such as monocyte chemoattractant protein-1 (MCP-1), and macrophage markers, such as cluster of differentiation 68 (CD68) [9][10][11][12]. Levels of anti-inflammatory markers such as Twist-related protein 1 (Twist1) and adiponectin are significantly lower in obese insulin-resistant than in nonobese insulin-sensitive people [13][14][15].…”

Adipose tissue inflammation and liver fat in patients with highly active antiretroviral therapy-associated lipodystrophy

“…Liver fat has been shown to be associated with increased gene expression of macrophage-specific cell surface markers such as CD68 (18,25) and an increased number of macrophages (10,18) in adipose tissue. Recently, this association has been shown to be independent of obesity (18,25).…”

“…Liver fat has been shown to be associated with increased gene expression of macrophage-specific cell surface markers such as CD68 (18,25) and an increased number of macrophages (10,18) in adipose tissue. Recently, this association has been shown to be independent of obesity (18,25). These data raise a possibility that inflammatory changes in adipose tissue regulate liver fat or vice versa (3,8) or that a common etiological factor regulates both liver fat and inflammation in adipose tissue.…”