J. Lundbom

Impaired Mitochondrial Biogenesis in Adipose Tissue in Acquired Obesity

Low mitochondrial number and activity have been suggested as underlying factors in obesity, type 2 diabetes, and metabolic syndrome. However, the stage at which mitochondrial dysfunction manifests in adipose tissue after the onset of obesity remains unknown. Here we examined subcutaneous adipose tissue (SAT) samples from healthy monozygotic twin pairs, 22.8–36.2 years of age, who were discordant (ΔBMI >3 kg/m2, mean length of discordance 6.3 ± 0.3 years, n = 26) and concordant (ΔBMI <3 kg/m2, n = 14) for body weight, and assessed their detailed mitochondrial metabolic characteristics: mitochondrial-related transcriptomes with dysregulated pathways, mitochondrial DNA (mtDNA) amount, mtDNA-encoded transcripts, and mitochondrial oxidative phosphorylation (OXPHOS) protein levels. We report global expressional downregulation of mitochondrial oxidative pathways with concomitant downregulation of mtDNA amount, mtDNA-dependent translation system, and protein levels of the OXPHOS machinery in the obese compared with the lean co-twins. Pathway analysis indicated downshifting of fatty acid oxidation, ketone body production and breakdown, and the tricarboxylic acid cycle, which inversely correlated with adiposity, insulin resistance, and inflammatory cytokines. Our results suggest that mitochondrial biogenesis, oxidative metabolic pathways, and OXPHOS proteins in SAT are downregulated in acquired obesity, and are associated with metabolic disturbances already at the preclinical stage.

Adipocyte morphology and implications for metabolic derangements in acquired obesity

Background:Adipocyte size and number have been suggested to predict the development of metabolic complications in obesity. However, the genetic and environmental determinants behind this phenomenon remain unclear.Methods:We studied this question in rare-weight discordant (intra-pair difference (Δ) body mass index (BMI) 3–10 kg m−2, n=15) and concordant (ΔBMI 0–2 kg m−2, n=5) young adult (22–35 years) monozygotic twin pairs identified from 10 birth cohorts of Finnish twins (n=5 500 pairs). Subcutaneous abdominal adipocyte size from surgical biopsies was measured under a light microscope. Adipocyte number was calculated from cell size and total body fat (D × A).Results:The concordant pairs were remarkably similar for adipocyte size and number (intra-class correlations 0.91–0.92, P<0.01), suggesting a strong genetic control of these measures. In the discordant pairs, the obese co-twins (BMI 30.6±0.9 kg m−2) had significantly larger adipocytes (volume 547±59 pl), than the lean co-twins (24.9±0.9 kg m−2; 356±34 pl, P<0.001). In 8/15 pairs, the obese co-twins had less adipocytes than their co-twins. These hypoplastic obese twins had significantly higher liver fat (spectroscopy), homeostatic model assessment-index, C-reactive protein and low-density lipoprotein cholesterol than their lean co-twins. Hyperplastic obesity was observed in the rest (7/15) of the pairs, obese and lean co-twins having similar metabolic measures. In all pairs, Δadipocyte volume correlated positively and Δcell number correlated negatively with Δhomeostatic model assessment-index and Δlow-density lipoprotein, independent of Δbody fat. Transcripts most significantly correlating with Δadipocyte volume were related to a reduced mitochondrial function, membrane modifications, to DNA damage and cell death.Conclusions:Together, hypertrophy and hypoplasia in acquired obesity are related to metabolic dysfunction, possibly through disturbances in mitochondrial function and increased cell death within the adipose tissue.

Deep subcutaneous adipose tissue is more saturated than superficial subcutaneous adipose tissue.

Upper body abdominal subcutaneous adipose tissue (SAT) can be divided into deep SAT (DSAT) and superficial SAT (SSAT) depots. Studies on adipose tissue fatty acid (FA) composition have made no distinction between these two depots. The aim of this study is to determine whether DSAT and SSAT differ in FA composition. We studied the FA composition of DSAT and SSAT in 17 male and 13 female volunteers using non-invasive proton magnetic resonance spectroscopy in vivo. Magnetic resonance imaging was used to differentiate between DSAT and SSAT. Adipose tissue spectra were analysed for lipid unsaturation, or double bond (DB) content, and polyunsaturation (PU), according to previously validated methods. The DSAT depot was more saturated than the SSAT depot, in both men (0.833±0.012 vs 0.846±0.009 DB, P<0.002) and women (0.826±0.018 vs 0.850±0.018 DB, P<0.002). In contrast, PU did not differ between DSAT and SSAT in either men (0.449±0.043 vs 0.461±0.044 PU, P=0.125) or women (0.411±0.070 vs 0.442±0.062 PU, P=0.234) and displayed a close correlation between the depots (R=0.908, P<0.001, n=30). The higher saturation in DSAT compared with SSAT can be attributed to a higher ratio of saturated to monounsaturated FAs. These results should be taken into account when determining the FA composition of SAT.

CB(1) blockade-induced weight loss over 48 weeks decreases liver fat in proportion to weight loss in humans.

Objective:Studies in mice have suggested that endocannabinoid blockade using the cannabinoid receptor type 1 (CB1) blocker rimonabant prevents obesity-induced hepatic steatosis.Design and subjects:To determine effects of rimonabant on liver fat in humans, we measured liver fat content by proton magnetic resonance spectroscopy in 37 subjects who used either a CB1 blocker rimonabant or placebo in a double-blind, randomized manner. This was retrospectively compared with a historical hypocaloric diet weight loss group (n=23).Results:Weight loss averaged 8.5±1.4 kg in the rimonabant, 1.7±1.0 kg in the placebo and 7.5±0.2 kg in the hypocaloric diet group (P<0.001, rimonabant vs placebo; NS, rimonabant vs hypocaloric diet). Liver fat decreased more in the rimonabant (5.9% (2.5–14.6%) vs 1.8% (0.9–3.5%), before vs after) than in the placebo group (6.8% (2.2–15.7%) vs 4.9% (1.6–7.8%), before vs after, P<0.05). The percentage change in body weight correlated closely with the percentage loss of liver fat (r=0.70, P>0.0001). The decreases in liver fat were comparable between the rimonabant and the young historical hypocaloric diet groups.Conclusions:We conclude that, unlike in mice, in humans rimonabant decreases liver fat in proportion to weight loss.

Gene expression profile of subcutaneous adipose tissue in BMI-discordant monozygotic twin pairs unravels molecular and clinical changes associated with sub-types of obesity

Background:Subcutaneous adipose tissue (SAT) undergoes major changes in obesity, but little is known about the whole-genome scale patterns of these changes or about their variation between different obesity sub-groups. We sought to compare how transcriptomics profiles in SAT differ between monozygotic (MZ) co-twins who are discordant for body mass index (BMI), whether the profiles vary between twin pairs and whether the variation can be linked to clinical characteristics.Methods:We analysed the transcriptomics (Affymetrix U133 Plus 2.0) patterns of SAT in young MZ twin pairs (n=26, intra-pair difference in BMI >3 kg m−2, aged 23–36), from 10 birth cohorts of adult Finnish twins. The clinical data included measurements of body composition, insulin resistance, lipids and adipokines.Results:We found 2108 genes differentially expressed (false discovery rate (FDR)<0.05) in SAT of the BMI-discordant pairs. Pathway analyses of these genes revealed a significant downregulation of mitochondrial oxidative pathways (P<0.05) and upregulation of inflammation pathways (P<0.05). Hierarchical clustering of heavy/lean twin ratios, representing effects of acquired obesity in the transcriptomics data, revealed three sub-groups with different molecular profiles (FDR<0.05). Analyses comparing these sub-groups showed that, in the heavy co-twins, downregulation of the mitochondrial pathways, especially that of branched chain amino acid degradation was more evident in two clusters while and upregulation of the inflammatory response was most evident in the last, presumably the unhealthiest cluster. High-fasting insulin levels and large adipocyte diameter were the predominant clinical characteristic of the heavy co-twins in this cluster (Bonferroni-adjusted P<0.05).Conclusions:This is the first study in BMI-discordant MZ twin pairs reporting sub-types of obesity based on both SAT gene expression profiles and clinical traits. We conclude that a decrease in mitochondrial BCAA degradation and an increase in inflammation in SAT co-occur and associate with hyperinsulinemia and large adipocyte size in unhealthy obesity.

Acquired liver fat is a key determinant of serum lipid alterations in healthy monozygotic twins

Objective: The effects of acquired obesity on lipid profile and lipoprotein composition in rare BMI‐discordant monozygotic (MZ) twin pairs were studied.

Electrocardiographic changes associated with insulin resistance

BACKGROUND AND AIM Cardiac steatosis has been related to increased risk of heart disease. We investigated the association between cardiac steatosis, electrocardiographic (ECG) abnormalities, and individual components of the metabolic syndrome (MetS). METHODS AND RESULTS A 12-lead ECG and laboratory data were examined in 31 men with the MetS and in 38 men without the MetS. Myocardial triglyceride (MTG) content was measured with 1.5 T magnetic resonance (MR) spectroscopy and epicardial and pericardial fat by MR imaging. MTG content, epicardial and pericardial fat depots were higher in men with the MetS compared with subjects without the MetS (p < 0.001). The heart rate was increased (p < 0.001), the PR interval was longer (p < 0.044), the frontal plane QRS axis shifted to the left (p < 0.001), and the QRS voltage (p < 0.001) was lower in subjects with the MetS. The frontal plane QRS axis and the QRS voltage were inversely correlated with MTG content, waist circumference (WC), body mass index (BMI), TGs, and fasting blood glucose. High-density lipoprotein cholesterol correlated positively and measures of insulin resistance negatively with the QRS voltage. MTG content and hypertriglyceridemia were determinants of the frontal plane QRS and WC and hyperglycemia were predictors of the QRS voltage. CONCLUSION The MetS and cardiac steatosis appear to associate with multiple changes on 12-lead ECG. The frontal plane QRS axis is shifted to the left and the QRS voltage is lower in subjects with the MetS. Standard ECG criteria may underestimate the presence of left ventricular hypertrophy in obese subjects with cardiometabolic risk factors.

Biomarkers and prediction of myocardial triglyceride content in non-diabetic men.

BACKGROUND AND AIMS Lipid oversupply to cardiomyocytes or decreased utilization of lipids leads to cardiac steatosis. We aimed to examine the role of different circulating metabolic biomarkers as predictors of myocardial triglyceride (TG) content in non-diabetic men. METHODS AND RESULTS Myocardial and hepatic TG contents were measured with 1.5 T magnetic resonance (MR) spectroscopy, and LV function, visceral adipose tissue (VAT), abdominal subcutaneous tissue (SAT), epicardial and pericardial fat by MR imaging in 76 non-diabetic men. Serum concentration of circulating metabolic biomarkers [adiponectin, leptin, adipocyte-fatty acid binding protein 4 (A-FABP 4), resistin, and lipocalin-2] including β-hydroxybuturate (β-OHB) were measured. Subjects were stratified by tertiles of myocardial TG into low, moderate, and high myocardial TG content groups. Concentrations of β-OHB were lower (p = 0.003) and serum levels of A-FABP 4 were higher (p < 0.001) in the group with high myocardial TG content compared with the group with low myocardial TG content. β-OHB was negatively correlated with myocardial TG content (r = -0.316, p = 0.006), whereas A-FABP 4 was not correlated with myocardial TG content (r = 0.192, p = 0.103). In multivariable analyses β-OHB and plasma glucose levels were the best predictors of myocardial TG content independently of VAT and hepatic TG content. The model explained 58.8% of the variance in myocardial TG content. CONCLUSION Our data showed that β-OHB and fasting glucose were the best predictors of myocardial TG content in non-diabetic men. These data suggest that hyperglycemia and alterations in lipid oxidation may be associated with cardiac steatosis in humans.

Acquired Liver Fat Is A Key Determinant of Serum Lipid Alterations in Healthy Monozygotic Twins

Objective: The effects of acquired obesity on lipid profile and lipoprotein composition in rare BMI‐discordant monozygotic (MZ) twin pairs were studied.

Acquired liver fat is a key determinant of serum lipid alterations in healthy monozygotic twins: Liver Fat and Lipid Alterations-A Twin Study

Objective: The effects of acquired obesity on lipid profile and lipoprotein composition in rare BMI‐discordant monozygotic (MZ) twin pairs were studied.