Impact of Orlistat-Induced Weight Loss on Diastolic Function and Heart Rate Variability in Severely Obese Subjects with Diabetes

Objective. Determine the impact of Orlistat-induced weight loss on metabolic profile and cardiovascular function in severely obese patients with type 2 diabetes. Methods. Twenty-nine patients were randomized either to a nonplacebo control group or to a treatment group with Orlistat thrice a day. Metabolic profile, anthropometric parameters, heart rate variability indices, and echocardiographic variables were measured before and after a 12-week treatment period. Results. Treatment with Orlistat induced a modest but significant weight loss compared to controls (3.7 ± 3.0 versus 0.5 ± 2.2 kg, resp.; P = .003). There was significant decrease in fasting glycemia (7.9 ± 3.0 versus 6.7 ± 2.2 mmol/L; P = .03) and significant improvements in left ventricular diastolic function (P = .03) and in the sympathovagal balance (LF/HF ratio) (P = .04) in the Orlistat group. Conclusion. These results suggest that a modest weight loss improves fasting glycemia, left ventricular diastolic function, and sympathovagal balance in severely obese patients with type 2 diabetes

Characterization of dedifferentiating human mature adipocytes from the 6 visceral and subcutaneous fat compartments : fibroblast-activation protein 7 alpha and Dipeptidyl peptidase 4 as major components of matrix remodeling

Mature adipocytes can reverse their phenotype to become fibroblast-like cells. This is achieved by ceiling culture and the resulting cells, called dedifferentiated fat (DFAT) cells, are multipotent. Beyond the potential value of these cells for regenerative medicine, the dedifferentiation process itself raises many questions about cellular plasticity and the pathways implicated in cell behavior. This work has been performed with the objective of obtaining new information on adipocyte dedifferentiation, especially pertaining to new targets that may be involved in cellular fate changes. To do so, omental and subcutaneous mature adipocytes sampled from severely obese subjects have been dedifferentiated by ceiling culture. An experimental design with various time points along the dedifferentiation process has been utilized to better understand this process. Cell size, gene and protein expression as well as cytokine secretion were investigated. Il-6, IL-8, SerpinE1 and VEGF secretion were increased during dedifferentiation, whereas MIF-1 secretion was transiently increased. A marked decrease in expression of mature adipocyte transcripts (PPARγ2, C/EBPα, LPL and Adiponectin) was detected early in the process. In addition, some matrix remodeling transcripts (FAP, DPP4, MMP1 and TGFβ1) were rapidly and strongly up-regulated. FAP and DPP4 proteins were simultaneously induced in dedifferentiating mature adipocytes supporting a potential role for these enzymes in adipose tissue remodeling and cell plasticity

Comparison of the dipeptidyl peptidase-4 gene methylation levels between severely obese subjects with and without the metabolic syndrome

Background : The dipeptidyl peptidase-4 (DPP4) enzyme is a novel adipokine potentially involved in the development of the metabolic syndrome (MetS). Previous observations demonstrated higher visceral adipose tissue (VAT) DPP4 gene expression in non-diabetic severely obese men with (MetS+) vs. without (MetS−) MetS. DPP4 mRNA abundance in VAT correlated also with CpG site methylation levels (%Meth) localized within and near its exon 2 (CpG94 to CpG102) in non-diabetic severely obese women, regardless of their MetS status. The actual study tested whether DPP4 %Meth levels in VAT are different between MetS− and MetS+ non-diabetic severely obese subjects, whether variable metabolic and plasma lipid profiles are observed between DPP4 %Meth quartiles, and whether correlation exists in DPP4 %Meth levels between VAT and white blood cells (WBCs). Methods : DNA was extracted from the VAT of 26 men (MetS−: n=12, MetS+: n=14) and 79 women (MetS−: n=60; MetS+: n=19), as well as from WBCs in a sub-sample of 17 women (MetS−: n=9; MetS+: n=8). The %Meth levels of CpG94 to CpG102 were assessed by pyrosequencing of sodium bisulfite-treated DNA. ANOVA analyses were used to compare the %Meth of CpGs between MetS− and MetS+ groups, and to compare the metabolic phenotype and plasma lipid levels between methylation quartiles. Pearson correlation coefficient analyses were computed to test the relationship between VAT and WBCs CpG94-102 %Meth levels. Results : No difference was observed in CpG94-102 %Meth levels between MetS− and MetS+ subjects in VAT (P=0.67), but individuals categorized into CpG94-102 %Meth quartiles had variable plasma total-cholesterol concentrations (P=0.04). The %Meth levels of four CpGs in VAT were significantly correlated with those observed in WBCs (r=0.55−0.59, P≤0.03). Conclusions : This study demonstrated that %Meth of CpGs localized within and near the exon 2 of the DPP4 gene in VAT are not associated with MetS status. The actual study also revealed an association between the %Meth of this locus with plasma total-cholesterol in severe obesity, which suggests a link between the DPP4 gene and plasma lipid levels

DUSP1 gene polymorphisms are associated with obesity-related metabolic complications among severely obese patients and impact on gene methylation and expression

The DUSP1 gene encodes a member of the dual-specificity phosphatase family previously identified as being differentially expressed in visceral adipose tissue (VAT) of severely obese men with versus without the metabolic syndrome. Objective. To test the association between DUSP1 polymorphisms, obesity-related metabolic complications, gene methylation, and expression levels in VAT. Methods. The DUSP1 locus and promoter region were sequenced in 25 individuals. SNPs were tested for association with obesity-related complications in a cohort of more than 1900 severely obese individuals. The impact of SNPs on methylation levels of 36 CpG sites and correlations between DNA methylation and gene expression levels in VAT were computed in a subset of 14 samples. Results. Heterozygotes for rs881150 had lower HDL-cholesterol levels (HDL-C; = 0.01), and homozygotes for the minor allele of rs13184134 and rs7702178 had increased fasting glucose levels ( = 0.04 and 0.01, resp.). rs881150 was associated with methylation levels of CpG sites located ∼1250 bp upstream the transcription start site. Methylation levels of 4 CpG sites were inversely correlated with DUSP1 gene expression. Conclusion.These results suggest that DUSP1 polymorphisms modulate plasma glucose and HDL-C levels in obese patients possibly through alterations of DNA methylation and gene expression levels

Metabolic and cardiovascular improvements after biliopancreatic diversion in a severely obese patient

BACKGROUND: Severe obesity is associated with important morbidity and increased mortality. The successes of lifestyle modifications and drug therapy have been partial and mostly unsustained in reducing obesity and its comorbidities. Bariatric surgery, particularly biliopancreatic diversion with duodenal switch reduces efficiently excess body weight and improves metabolic and cardiovascular functions. CASE PRESENTATION: A 56-year-old man with severe clinical obesity underwent a biliopancreatic diversion with a duodenal switch after unsuccessful treatment with weight loss pharmacotherapy. He had diabetes, hypertension and sleep apnea syndrome and was on three medications for hypertension and two hypoglycemic agents in addition to > 200 insulin units daily. Eleven months after the surgery, he had lost 40% of his body weight. The lipid profile showed great improvement and the hypertension and diabetes were more easily controlled with no more insulin needed. The pseudonormalized pattern of left ventricular diastolic function improved and ventricular walls showed decreased thickness. CONCLUSION: Biliopancreatic diversion may bring metabolic and cardiovascular benefits in severely obese patients from a cardiovascular perspective

Increased adipose tissue indices of androgen catabolism and aromatization in women with metabolic dysfunction

Abstract Background Body fat distribution is a risk factor for obesity-associated comorbidities, and adipose tissue dysfunction plays a role in this association. In humans, there is a sex difference in body fat distribution, and steroid hormones are known to regulate several cellular processes within adipose tissue. Our aim was to investigate if intra-adipose steroid concentration and expression or activity of steroidogenic enzymes were associated with features of adipose tissue dysfunction in individuals with severe obesity. Methods Samples from 40 bariatric candidates (31 women, 9 men) were included in the study. Visceral (VAT) and subcutaneous adipose tissue (SAT) were collected during surgery. Adipose tissue morphology was measured by a combination of histological staining and semi-automated quantification. Following extraction, intra-adipose and plasma steroid concentrations were determined by liquid chromatography, electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Aromatase activity was estimated using product-over-substrate ratio, while AKR1C2 activity was measured directly by fluorogenic probe. Gene expression was measured by quantitative PCR. Results VAT aromatase activity was positively associated with VAT adipocyte hypertrophy (p-valueadj < 0.01) and negatively with plasma HDL-cholesterol (p-valueadj < 0.01), while SAT aromatase activity predicted dyslipidemia in women even after adjustment for waist circumference, age and hormonal contraceptive use. We additionally compared women with high and low visceral adiposity index (VAI) and found that VAT excess is characterized by adipose tissue dysfunction, increased androgen catabolism mirrored by increased AKR1C2 activity and higher aromatase expression and activity indices. Conclusion In women, increased androgen catabolism or aromatization is associated with visceral adiposity and adipose tissue dysfunction

Use of blood as a surrogate model for the assessment of visceral adipose tissue methylation profiles associated with the metabolic syndrome in men

Epigenetic mechanisms are known to be involved in tissue-specific differentiation. DNA methylation patterns have been shown to be largely conserved across tissues but with variation for specific genes. However, it is unclear whether the variability observed in the methylation profile of a metabolically active tissue is reflected in other sources such as hematopoietic tissue. This study aimed to test blood genome-wide CpG site methylation levels as a surrogate model for visceral adipose tissue (VAT) methylation and to verify whether it appropriately reflects differences in methylation levels found in VAT between men discordant for the metabolic syndrome (MetS). Tissue specimens (VAT and blood samples) were obtained from 16 severely obese individuals discordant for the MetS. CpG sites methylation levels were measured with the Infinium HumanMethylation450 BeadChip and correlations of methylation levels between VAT and blood were computed. Differences in methylation levels between individuals with and without MetS were tested in both tissues. Pathway analysis was conducted for differentially methylated CpG sites common to both tissues. High cross-tissue correlations were observed for VAT and blood (0.952±0.014) while some CpG sites had significantly different methylation levels in VAT versus blood. Differential methylation analysis between individuals with and without MetS demonstrated a higher number of differentially methylated CpG sites in VAT than in blood (11,778 vs. 881, respectively) with nearly 4% of differentially methylated sites found in VAT being also represented in blood. Common differentially methylated sites were involved in inflammatory-, lipid- and diabetes-related pathways. These results suggest that blood methylation levels of specific CpG sites may adequately reflect VAT methylation levels for some of the MetS-related genes, specifically for inflammatory, lipid and glucose metabolism genes