Hannele Yki-Järvinen

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. 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.

Acute in vivo effects of insulin on gene expression in adipose tissue in insulin-resistant and insulin-sensitive subjects

Aims/hypothesisWe determined the response of selected genes to in vivo insulin in adipose tissue in 21 non-diabetic women.Materials and methodsThe women were divided into insulin-sensitive and -resistant groups based on their median whole-body insulin sensitivity (8.7±0.4 vs 4.2±0.3xa0mg kg−1xa0min−1 for insulin-sensitive vs -resistant group). Subcutaneous adipose tissue biopsies were obtained before and after 3 and 6xa0h of i.v. maintained euglycaemic hyperinsulinaemia. Adipose tissue mRNA concentrations of facilitated glucose transporter, member 1 (SLC2A1, previously known as GLUT1), facilitated glucose transporter, member 4 (SLC2A4, previously known as GLUT4), peroxisome proliferator-activated receptor γ ( PPARG), peroxisome proliferator-activated receptor γ co-activator 1α (PPARGC1A), 11β-hydroxysteroid dehydrogenase-1 (HSD11B1), TNF, adiponectin (ADIPOQ), IL6 and the macrophage marker CD68 were measured using real-time PCR.ResultsBasal expression of ‘insulin-sensitivity genes’ SLC2A4 and ADIPOQ was lower while that of ‘insulin-resistance genes’, HSD11B1 and IL6 was significantly higher in the insulin-resistant than in the insulin-sensitive group. Insulin significantly increased expression of ‘insulin-sensitivity genes’ SLC2A4, PPARG, PPARGC1A and ADIPOQ in the insulin-sensitive group, while only expression of PPARG and PPARGC1A was increased in the insulin-resistant group. The expression of ‘insulin-resistance genes’ HSD11B1 and IL6 was increased by insulin in the insulin-resistant group, but insulin failed to increase HSD11B1 expression in the insulin-sensitive group. At 6xa0h, expression of HSD11B1, TNF and IL6 was significantly higher in the insulin-resistant than in the insulin-sensitive group. IL6 expression increased significantly more in response to insulin in the insulin-resistant than in the insulin-sensitive group. CD68 was overexpressed in the insulin-resistant as compared with the insulin-sensitive group at both 0 and 6xa0h.Conclusions/interpretationThese data suggest that genes adversely affecting insulin sensitivity hyperrespond to insulin, while genes enhancing insulin sensitivity hyporespond to insulin in insulin-resistant human adipose tissue in vivo.

In the lipodystrophy associated with highly active antiretroviral therapy, pseudo-Cushing’s syndrome is associated with increased regeneration of cortisol by 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue

Aims/hypothesisHighly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV) is associated with a poorly understood lipodystrophic and hypertriglyceridaemic syndrome, which resembles Cushing’s syndrome, but in which plasma cortisol is not elevated. We tested the hypothesis that this HAART-associated lipodystrophy is explained by increased local regeneration of cortisol from inactive cortisone within adipose tissue, catalysed by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1).MethodsIn this cross-sectional study, a previously described cohort of 30 HIV-infected patients with lipodystrophy were compared with 13 HIV-infected patients without lipodystrophy. Intra-abdominal and subcutaneous adipose tissue were quantified using magnetic resonance imaging. Gene expression in subcutaneous fat was measured using real-time PCR. Urine cortisol and its metabolites were analysed by gas chromatography/mass spectrometry.ResultsPatients with lipodystrophy had significantly higher 11β-HSD1 mRNA concentrations (relative to β2-microglobulin mRNA) in subcutaneous adipose tissue than non-lipodystrophic patients (0.29±0.20 vs 0.09±0.07, p=0.0004) and higher ratios of urinary cortisolxa0:xa0cortisone metabolites. Adipose tissue 11β-HSD1 mRNA correlated with multiple features of insulin resistance and with mRNA concentrations for glucocorticoid receptor and angiotensinogen.Conclusions/interpretationIn adipose tissue of patients with HAART-associated lipodystrophy, 11β-HSD1 mRNA is increased and its concentration is correlated with features of insulin resistance. We suggest that increased adipose tissue 11β-HSD1 may explain the pseudo-Cushing’s features in patients with HAART-associated lipodystrophy, and is a potential therapeutic target.

Exploring the lipoprotein composition using Bayesian regression on serum lipidomic profiles

MOTIVATIONnSerum lipids have been traditionally studied in the context of lipoprotein particles. Todays emerging lipidomics technologies afford sensitive detection of individual lipid molecular species, i.e. to a much greater detail than the scale of lipoproteins. However, such global serum lipidomic profiles do not inherently contain any information on where the detected lipid species are coming from. Since it is too laborious and time consuming to routinely perform serum fractionation and lipidomics analysis on each lipoprotein fraction separately, this presents a challenge for the interpretation of lipidomic profile data. An exciting and medically important new bioinformatics challenge today is therefore how to build on extensive knowledge of lipid metabolism at lipoprotein levels in order to develop better models and bioinformatics tools based on high-dimensional lipidomic data becoming available today.nnnRESULTSnWe developed a hierarchical Bayesian regression model to study lipidomic profiles in serum and in different lipoprotein classes. As a background data for the model building, we utilized lipidomic data for each of the lipoprotein fractions from 5 subjects with metabolic syndrome and 12 healthy controls. We clustered the lipid profiles and applied a regression model within each cluster separately. We found that the amount of a lipid in serum can be adequately described by the amounts of lipids in the lipoprotein classes. In addition to improved ability to interpret lipidomic data, we expect that our approach will also facilitate dynamic modelling of lipid metabolism at the individual molecular species level.

Diabetes and Arterial Stiffness

Many clinicians continue to view diabetes mellitus as essentially an endocrine disease associated with hyperglycemia. Although the risk of developing specific complications of diabetes such as retinopathy, nephropathy and neuropathy is clearly associated with the degree (and duration) of hyperglycemia, the relationship between diabetes and macrovascular disease remains poorly understood (1,2). However, among patients with type 2 diabetes mellitus, the most common cause of death is cardiovascular disease (3). Improved glycemic control reduces microvascular complications in both types 1 and 2 diabetes, but requires many years of intensive treatment (4,5). However, The UK Prospective Diabetes Study (UKPDS) demonstrated unequivocally that improved glycemic control alone is insufficient to reduce the incidence of diabetic macrovascular complications (stroke and myocardial infarction) in patients with type 2 diabetes (5). Conversely, more aggressive lowering of blood pressure reduces the incidence of stroke and overall mortality amongst patients with type 2 diabetes (6). Perhaps, unsurprisingly, blood pressure lowering is also more effective in reducing the incidence of diabetic retinopathy than aggressive glycemic control (6). Moreover, cholesterol reduction also reduces macrovascular disease and mortality in diabetic patients (7). Taken together, these findings reinforce the concept of diabetes as a vascular disease.