Identification of circulating apolipoprotein M as a new determinant of insulin sensitivity and relationship with adiponectin.

BACKGROUND: The adiponectin is one of the rare adipokines down-regulated with obesity and protects against obesity-related disorders. Similarly, the apolipoprotein M (apoM) is expressed in adipocytes and its expression in adipose tissue is associated with metabolic health. We compared circulating apoM with adiponectin regarding their relationship with metabolic parameters and insulin sensitivity and examined their gene expression patterns in adipocytes and in the adipose tissue. METHODS: Circulating apoM and adiponectin were examined in 169 men with overweight in a cross-sectional study, and 13 patients with obesity during a surgery-induced slimming program. Correlations with clinical parameters including the insulin resistance index (HOMA-IR) were analyzed. Multiple regression analyses were performed on HOMA-IR. The APOM and ADIPOQ gene expression were measured in the adipose tissue from 267 individuals with obesity and a human adipocyte cell line. RESULTS: Participants with type 2 diabetes had lower circulating adiponectin and apoM, while apoM was higher in individuals with dyslipidemia. Similar to adiponectin, apoM showed negative associations with HOMA-IR and hs-CRP (r < -0.2), and positive correlations with HDL markers (HDL-C and apoA-I, r > 0.3). Unlike adiponectin, apoM was positively associated with LDL markers (LDL-C and apoB100, r < 0.20) and negatively correlated with insulin and age (r < -0.2). The apoM was the sole negative determinant of HOMA-IR in multiple regression models, while adiponectin not contributing significantly. After surgery, the change in HOMA-IR was negatively associated with the change in circulating apoM (r = -0.71), but not with the change in adiponectin. The APOM and ADIPOQ gene expression positively correlated in adipose tissue (r > 0.44) as well as in adipocytes (r > 0.81). In adipocytes, APOM was downregulated by inflammatory factors and upregulated by adiponectin. CONCLUSIONS: The apoM rises as a new partner of adiponectin regarding insulin sensitivity. At the adipose tissue level, the adiponectin may be supported by apoM to promote a healthy adipose tissue. TRIAL REGISTRATION: NCT01277068, registered 13 January 2011; NCT02332434, registered 5 January 2015; and NCT00390637, registered 20 October 2006.

Low Density Lipoprotein Cholesterol Decreases the Expression of Adenosine A2A Receptor and Lipid Rafts-Protein Flotillin-1: Insights on Cardiovascular Risk of Hypercholesterolemia.

High blood levels of low-density lipoprotein (LDL)-cholesterol (LDL-C) are associated with atherosclerosis, mainly by promoting foam cell accumulation in vessels. As cholesterol is an essential component of cell plasma membranes and a regulator of several signaling pathways, LDL-C excess may have wider cardiovascular toxicity. We examined, in untreated hypercholesterolemia (HC) patients, selected regardless of the cause of LDL-C accumulation, and in healthy participants (HP), the expression of the adenosine A2A receptor (A2AR), an anti-inflammatory and vasodilatory protein with cholesterol-dependent modulation, and Flotillin-1, protein marker of cholesterol-enriched plasma membrane domains. Blood cardiovascular risk and inflammatory biomarkers were measured. A2AR and Flotillin-1 expression in peripheral blood mononuclear cells (PBMC) was lower in patients compared to HP and negatively correlated to LDL-C blood levels. No other differences were observed between the two groups apart from transferrin and ferritin concentrations. A2AR and Flotillin-1 proteins levels were positively correlated in the whole study population. Incubation of HP PBMCs with LDL-C caused a similar reduction in A2AR and Flotillin-1 expression. We suggest that LDL-C affects A2AR expression by impacting cholesterol-enriched membrane microdomains. Our results provide new insights into the molecular mechanisms underlying cholesterol toxicity, and may have important clinical implication for assessment and treatment of cardiovascular risk in HC.

Bariatric Surgery Improves the Atherogenic Profile of Circulating Methylarginines in Obese Patients: Results from a Pilot Study.

Bariatric surgery improves obesity-related comorbidities. Methylarginines are biomarkers of cardiometabolic risk, liver steatosis, and insulin resistance. Here, we aimed to investigate methylarginines in obese patients undergoing bariatric surgery and compared them to age- and sex-matched healthy subjects. Thirty-one obese patients who underwent bariatric surgery and 31 healthy individuals were used for this retrospective study. The basal serum methylarginine levels were determined in the healthy individuals and the obese patients, before surgery and 6 and 12 months after surgery, by mass spectrometry. Compared with the healthy individuals, the obese patients displayed elevated monomethylarginine (mean change: +95%, p < 0.001), asymmetric-dimethylarginine (+105%, p < 0.001), symmetric-dimethylarginine (+25%, p = 0.003), and dimethylguanidino valerate (+32%, p = 0.008) concentrations. Bariatric surgery durably reduced the body mass index by 28% (12 months, 95%CI: 24-33, p = 0.002) and improved plasma lipids, insulin resistance, and liver function. Bariatric surgery reduced the serum levels of monomethylarginine and asymmetric-dimethylarginine by 12% (95%CI: 6-17) and 36% (95%CI: 27-45) (12 months, p = 0.003), respectively, but not symmetric-dimethylarginine or dimethylguanidino valerate. The monomethylarginine and asymmetric-dimethylarginine concentrations were strongly correlated with markers of dyslipidemia, insulin resistance, and a fatty liver. Serum dimethylguanidino valerate was primarily correlated with glycemia and renal function, whereas serum symmetric-dimethylarginine was almost exclusively associated with renal function. In conclusion, the monomethylarginine and asymmetric-dimethylarginine levels are efficiently decreased by bariatric surgery, leading to a reduced atherogenic profile in obese patients. Methylarginines follow different metabolic patterns, which could help for the stratification of cardiometabolic disorders in obese patients.

Draft genome and description of Negativicoccus massiliensis strain Marseille-P2082, a new species isolated from the gut microbiota of an obese patient.

Strain Marseille-P2082, an anaerobic, non-motile, asporogenous, Gram-negative, coccoid bacterium was isolated from the faeces of a 33 year-old obese French woman before bariatric surgery. The isolate exhibits 98.65% 16S rRNA gene nucleotide sequence similarity with Negativicoccus succinicivorans strain ADV 07/08/06-B-1388T, its current closest phylogenetic neighbour with standing in nomenclature. However, the dDDH relatedness between the new isolate and N. succinicivorans type strain ADV 07/08/06-B-1388T is 52.5 ± 2.7%. Strain Marseille-P2082 has a genome of 1,360,589 bp with a 51.1% G+C content. Its major fatty acids were identified as C18:1n9, C18:0 and C16:0. Based on its phenotypic, genomic and phylogenetic characteristics, strain Marseille-P2082T [= CSURP2082 (Collection de Souches de l'Unité des Rickettsies) = DSM 100853] is proposed as the type strain of the novel species Negativicoccus massiliensis sp. nov. The 16S rRNA gene sequence and whole-genome shotgun sequence have been deposited in EMBL-EBI under accession numbers LN876651 and LT700188, respectively.

Increased levels of the megakaryocyte and platelet expressed cysteine proteases stefin A and cystatin A prevent thrombosis.

Increased platelet activity occurs in type 2 diabetes mellitus (T2DM) and such platelet dysregulation likely originates from altered megakaryopoiesis. We initiated identification of dysregulated pathways in megakaryocytes in the setting of T2DM. We evaluated through transcriptomic analysis, differential gene expressions in megakaryocytes from leptin receptor-deficient mice (db/db), exhibiting features of human T2DM, and control mice (db/+). Functional gene analysis revealed an upregulation of transcripts related to calcium signaling, coagulation cascade and platelet receptors in diabetic mouse megakaryocytes. We also evidenced an upregulation (7- to 9.7-fold) of genes encoding stefin A (StfA), the human ortholog of Cystatin A (CSTA), inhibitor of cathepsin B, H and L. StfA/CSTA was present in megakaryocytes and platelets and its expression increased during obesity and diabetes in rats and humans. StfA/CSTA was primarily localized at platelet membranes and granules and was released upon agonist stimulation and clot formation through a metalloprotease-dependent mechanism. StfA/CSTA did not affect platelet aggregation, but reduced platelet accumulation on immobilized collagen from flowing whole blood (1200 s-1). In-vivo, upon laser-induced vascular injury, platelet recruitment and thrombus formation were markedly reduced in StfA1-overexpressing mice without affecting bleeding time. The presence of CA-074Me, a cathepsin B specific inhibitor significantly reduced thrombus formation in-vitro and in-vivo in human and mouse, respectively. Our study identifies StfA/CSTA as a key contributor of platelet-dependent thrombus formation in both rodents and humans.

Effect of Nutrient and Micronutrient Intake on Chylomicron Production and Postprandial Lipemia.

Postprandial lipemia, which is one of the main characteristics of the atherogenic dyslipidemia with fasting plasma hypertriglyceridemia, low high-density lipoprotein cholesterol and an increase of small and dense low-density lipoproteins is now considered a causal risk factor for atherosclerotic cardiovascular disease and all-cause mortality. Postprandial lipemia, which is mainly related to the increase in chylomicron production, is frequently elevated in individuals at high cardiovascular risk such as obese or overweight patients, type 2 diabetic patients and subjects with a metabolic syndrome who share an insulin resistant state. It is now well known that chylomicron production and thus postprandial lipemia is highly regulated by many factors such as endogenous factors: circulating factors such as hormones or free fatty acids, genetic variants, circadian rhythms, or exogenous factors: food components, dietary supplements and prescription drugs. In this review, we focused on the effect of nutrients, micronutrients and phytochemicals but also on food structure on chylomicron production and postprandial lipemia.

Lipodystrophy-like features after total body irradiation among survivors of childhood acute leukemia.

BACKGROUND/OBJECTIVE: The number of long-term survivors of childhood acute leukemia (AL) is substantially growing. These patients are at high risk for metabolic syndrome (MS), especially those who received total body irradiation (TBI). The consequences of children's irradiation on adipose tissue (AT) development in adulthood are currently unknown. The objective of this study is to assess the impact of TBI on AT of childhood AL survivors. DESIGN: We compared the morphological and functional characteristics of AT among survivors of childhood AL who developed MS and received (n = 12) or not received (n = 12) TBI. SUBJECTS/METHODS: Body fat distribution and ectopic fat stores (abdominal visceral and liver fat) were evaluated by DEXA, MRI and 1H-spectroscopy. Functional characteristics of subcutaneous AT were investigated by studying gene expression and pre-adipocyte differentiation in culture. RESULTS: Patients who have received TBI exhibited a lower BMI (minus 5 kg/m2) and a lower waist circumference (minus 14 cm), especially irradiated women. Despite the lower quantity of intra-abdominal AT, irradiated patient displayed a nearly two-fold greater content of liver fat when compared to non-irradiated patient (17 vs 9%, P = 0.008). These lipodystrophic-like features are supplemented by molecular abnormalities in subcutaneous AT of irradiated patients: decrease of gene expression of SREBP1 (minus 39%, P = 0.01) and CIDEA (minus 36%, P = 0.004) and a clear alteration of pre-adipocyte differentiation. CONCLUSIONS: These results strongly support the direct effect of irradiation on AT, especially in women, leading to specific nonalcoholic fatty liver disease, despite lower BMI. A long-term appropriate follow-up is necessary for these patients.

Draft Genome and Description of Eisenbergiella massiliensis Strain AT11T: A New Species Isolated from Human Feces After Bariatric Surgery.

A novel strain of a Gram-stain negative, non-motile, non-spore forming rod-shaped, obligate anaerobic bacterium, designated AT11T, was isolated from a stool sample of a morbidly obese woman living in Marseille, France. This bacterium was characterized using biochemical, chemotaxonomic, and phylogenetic methods. The 16S rRNA gene sequence analysis showed that strain AT11T had a 97.8% nucleotide sequence similarity with Eisenbergiella tayi strain B086562T, the closest species with standing in nomenclature. The major cellular fatty acids of the novel isolate were C16:0 followed by saturated or unsaturated C18 fatty acids (C18:1n9, C18:1n5 and C18:0). The draft genome of strain AT11T is 7,114,554 bp long with 48% G+C content. 6176 genes were predicted, including 6114 protein-coding genes and 62 were RNAs (with 2 5S rRNA genes, two 16S rRNA genes, two 23S rRNA genes, and 56 tRNA genes). The digital DNA-DNA hybridization (dDDH) relatedness between the new isolate and E. tayi strain B086562T was 23.1% ± 2.2. Based on the phenotypic, chemotaxonomic, genomic, and phylogenetic characteristics, Eisenbergiella massiliensis sp. nov., is proposed. The type strain is AT11T (= DSM 100838T = CSUR P2478T).

One-year impact of bariatric surgery on serum anti-Mullerian-hormone levels in severely obese women.

INTRODUCTION: Although bariatric surgery seems to increase spontaneous fertility by improving ovulatory function in young women, its impact on ovarian reserve remains largely unknown. OBJECTIVE: To evaluate changes in serum anti-Mullerian hormone (AMH) levels in reproductive-age severely obese women after bariatric surgery (BS). METHODS: AMH levels were measured retrospectively in 39 women (mean age 34.6 ± 1.1 years, range 18-45) that underwent a sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB) at baseline, and 6 and 12 months after BS. Metabolic and micronutrient status, including fasting plasma insulin and glucose, HOMA-IR, leptin, adiponectin, calcium, albumin, transthyretin, ferritin, vitamins (B9, B12, B1, A, E, D), zinc, and selenium, were assessed in all patients before and 1 year after BS. RESULTS: Of the patients, 79% had class-3 obesity. At 6 and 12 months, mean total weight losses (TWL) were 26 and 30%; mean excess weight losses (EWL) were 61.7 and 70.2%. Compared to baseline, AMH levels significantly decreased by 18% at 6 months, and 32% at 12 months post-operatively (p = 0.010 and p = 0.001, respectively). There was no correlation between AMH variation and changes in metabolic parameters or micronutrient levels. Remarkably, changes in AMH levels did not differ between sleeve and RYGB patients and were not correlated with EWL. CONCLUSION: This pilot study shows a drastic reduction in AMH levels at 1 year after BS in reproductive-age severely obese women, which was not related to weight loss: this suggests a negative impact of BS on ovarian reserve, at least in the short term.

Impact of bariatric surgery on apolipoprotein C-III levels and lipoprotein distribution in obese human subjects.

BACKGROUND: Elevated apolipoprotein C-III (apoC-III) has been postulated to contribute to the atherogenic dyslipidemia seen in obesity and insulin-resistant states, mainly by impairing plasma triglyceride-rich lipoprotein (TRL) metabolism. Bariatric surgery is associated with improvements of several obesity-associated metabolic abnormalities, including a reduction in plasma triglycerides (TGs) and an increase in plasma high-density lipoprotein cholesterol (HDL-C). OBJECTIVES: We investigated the specific effect of bariatric surgery on apoC-III concentrations in plasma, non-HDL, and HDL fractions in relation to lipid profile parameters evolution. METHODS: A total of 132 obese subjects undergoing bariatric surgery, gastric bypass (n = 61) or sleeve gastrectomy (n = 71), were studied 1 month before surgery and 6 and 12 months after surgery. RESULTS: Plasma apoC-III, non-HDL-apoC-III, and HDL-apoC-III concentrations were markedly reduced after surgery and strongly associated with reduction in plasma TG. This decrease was accompanied by a redistribution of apoC-III from TRL to HDL fractions. In multivariate analysis, plasma apoC-III was the strongest predictor of TG reduction after surgery, and the increase of HDL-C was positively associated with plasma adiponectin and negatively with body mass index. CONCLUSION: Marked reduction of apoC-III and changes in its distribution between TRL and HDL consistent with a better lipid profile are achieved in obese patients after bariatric surgery. These apoC-III beneficial modifications may have implications in dyslipidemia improvement and contribute to cardiovascular risk reduction after surgery.

Effects of bariatric surgery on hepatic and intestinal lipoprotein particle metabolism in obese, nondiabetic humans.

OBJECTIVE: The dyslipidemia of obesity and other insulin-resistant states is characterized by the elevation of plasma triglyceride-rich lipoproteins (TRL) of both hepatic (apoB-100-containing very low-density lipoprotein) and intestinal (apoB-48-containing chylomicrons) origin. Bariatric surgery is a well-established and effective modality for the treatment of obesity and is associated with improvements in several metabolic abnormalities associated with obesity, including a reduction in plasma triglycerides. Here, we have investigated the effect of bariatric surgery on TRL metabolism. APPROACH AND RESULTS: Twenty-two nondiabetic, obese subjects undergoing bariatric surgery: sleeve gastrectomy (n=12) or gastric bypass (n=10) were studied. Each subject underwent 1 lipoprotein turnover study 1 month before surgery followed by a second study, 6 months after surgery, using established stable isotope enrichment methodology, in constant fed state. TRL-apoB-100 concentration was significantly reduced after sleeve gastrectomy, explained by a decrease (P<0.05) in TRL-apoB-100 production rate and an increase (P<0.05) in TRL-apoB-100 fractional catabolic rate. TRL-apoB-48 concentration was also significantly reduced after sleeve gastrectomy, explained by reduction in TRL-apoB-48 production rate (P<0.05). For gastric bypass, although TRL-apoB-100 concentration declined after surgery (P<0.01), without a significant decline in TRL-apoB-48, there was no significant change in either TRL-apoB-100 or TRL-apoB-48 production rate or fractional catabolic rate. The reduction in TRL-apoB-100 concentration was significantly associated with a reduction in plasma apoC-III in the pooled group of patients undergoing bariatric surgery. CONCLUSIONS: This is the first human lipoprotein kinetic study to explore the mechanism of improvement of TRL metabolism after bariatric surgery. These effects may contribute to the decrease of cardiovascular mortality after surgery. CLINICAL TRIAL REGISTRATION URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01277068.

LDL-cholesterol-lowering effect of a dietary supplement with plant extracts in subjects with moderate hypercholesterolemia.

PURPOSE: Red yeast rice (RYR), sugar cane-derived policosanols (SCdP) and artichoke leaf extracts (ALEs) are currently incorporated alone or in combination into dietary supplements for their potential low-density-lipoprotein cholesterol (LDL-cholesterol)-lowering effects. Yet, there is no information supporting the efficacy of this association on the reduction in LDL-cholesterol. The main objective of this study was to investigate the effects of a new dietary supplement (DS) with RYR, SCdP and ALEs on LDL-cholesterol. METHODS: In a double-blind, randomized, parallel controlled study, 39 subjects from 21 to 55 years with moderate hypercholesterolemia without drug treatment were assigned to 2 groups and then consumed either a DS containing RYR, SCdP and ALEs or a placebo over a 16-week period. Plasma concentrations of lipids [LDL-cholesterol, total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-cholesterol), triacylglycerols (TG)] and plasma levels of vitamins C and E, total polyphenols and malondialdehyde were determined at baseline and after 4, 8, 12 and 16 weeks. RESULTS: LDL-cholesterol and TC were reduced by, respectively, 21.4 % (95 % CI, -13.3 to -24.9 %, p < 0.001) and 14.1 % (95 % CI, -10.1 to -18.0 %, p < 0.001) at week 16 in the DS group compared with baseline. Similar results were obtained at weeks 4, 8 and 12. TG decreased by 12.2 % after 16 weeks in the DS group (95 % CI: -24.4 to -0.1 %, p < 0.05). For the vitamin E/TC ratio, a difference was observed between groups at week 16 (p < 0.05). Other parameters were not modified. CONCLUSIONS: Daily consumption of this new DS decreased LDL-cholesterol and TC and is therefore an interesting, convenient aid in managing mild to moderate hypercholesterolemia.

Patterns of gene expressions induced by arsenic trioxide in cultured human fibroblasts.

Arsenic exposure is associated with several human diseases and particularly, with neoplasia. Although the mechanism of arsenic toxicity is not fully understood, several recent works pointed out the involvement of oxidative stress in arsenic-induced DNA damage that, in living cells, correlates with changes in gene expressions. In cultured human fibroblasts exposed for 24 h to micromolar arsenic concentrations, we studied, using real-time RT-PCR, the expression profile of a limited number of genes: genes coding for a stress protein (HSP70), transcription factors (cJUN, cFOS, ETR103, ETR101 and TTP) and cell cycle or DNA repair proteins (P21, GADD153). We observed that the expression profile of genes followed individual different patterns that can be summed up in early-transient gene expression by contrast to delayed gene expression.