Muriel Coupaye

Serum amyloid A: a marker of adiposity-induced low-grade inflammation but not of metabolic status.

Objective: Adipocytes secrete a series of acute phase proteins including serum amyloid A (SAA); the link with metabolic status is unknown. We studied the variations of expression of the SAA gene in adipose and liver tissues and of SAA serum levels, as well as their relationships with metabolic features during weight loss.

Microparticle increase in severe obesity: Not related to metabolic syndrome and unchanged after massive weight loss

To clarify the relationships between circulating microparticles (MPs), leukocyte–platelet aggregates (LPAs), obesity, and metabolic abnormalities and evaluate the effect of losing weight on these parameters.

Long-term evolution of nutritional deficiencies after gastric bypass: an assessment according to compliance to medical care.

Objective:To study long-term nutritional deficits based on adherence to a standardized nutritional care after gastric bypass (GBP). Background:Long-term prospective data on nutritional complications after GBP are missing. It is not known whether severe deficiencies are prevented by standard multivitamin supplementation and what parameters are influenced by patient adherence to nutritional care. Design:One hundred forty-four consecutive subjects from our prospective database (90% women, initial body mass index: 48 ± 15 kg/m2, age: 43 ± 10 years) who underwent GBP more than 3 years before the study were assessed. Multivitamins were systematically prescribed after GBP, and additional supplements were introduced if deficiencies were recorded during follow-up. We identified a group of 66 compliant subjects who attended yearly medical visits and a group of 32 noncompliant subjects who were recalled because they had not attended any visit for more than 2 years. Results:Weight loss was 42 ± 14 kg at 3 years or later. The number of nutritional deficits per subject was 3.2 ± 2.3 before surgery and did not significantly increase between 1 and 3 years or later after GBP (3.4 ± 2.0 and 3.5 ± 2.3, respectively). However, specific nutritional deficits occurred despite long-term multivitamin supplementation, including vitamins B1, B12, and D and iron. Noncompliant subjects had more deficits than compliant subjects (4.2 ± 1.9 vs 2.9 ± 2.0 deficits per patient, P < 0.01) and the number of deficits correlated with the time from last visit (r = 0.285, P < 0.01). Conclusions:Lifelong medical care is required to maintain a good nutritional status after GBP. Monitoring of nutritional parameters is necessary to add supplementation for deficits that are not prevented by multivitamin preparations.

Growth Hormone Therapy for Children and Adolescents with Prader-Willi Syndrome Is Associated with Improved Body Composition and Metabolic Status in Adulthood

CONTEXT Children with Prader-Willi syndrome (PWS) who receive GH treatment have improved growth and body composition; however, data are lacking for adults when treatment is discontinued after completion of growth. OBJECTIVES Our aim was to compare body composition and metabolic status in adults with PWS according to GH treatment in childhood and adolescence. DESIGN 64 adults (mean age: 25.4 years) with a genetic diagnosis of PWS were evaluated: 20 received GH in childhood (T), which had been discontinued at the time of this study, and 44 did not receive GH (C). Mean duration of treatment in the T group was 4.4 ± 2.7 years, age at baseline was 11.8 ± 2.7 years, mean time between the end of treatment and the current evaluation was 7.0 ± 4.4 years. MAIN OUTCOMES MEASURES Dual-energy X-ray absorptiometry was used to assess body composition and fasting biological analyses evaluated metabolic status. RESULTS (MEAN ± SD): Body mass index and percentage of fat mass were significantly lower in the T group (32.4 ± 10.3 vs 41.2 ± 11.1 kg/m(2), P = 0.05 and 44.0 ± 9.6 vs 50.1 ± 7.2%, P = 0.02, respectively). Insulinemia and HOMA-IR in non-diabetic subjects were significantly lower in the T group (5.8 ± 5.9 vs 13.9 ± 11.6 μUI/ml, P = 0.03, and 1.6 ± 1.3 vs 2.7 ± 2.1, P = 0.04, respectively). Non-diabetic and diabetic subjects from the T group had a significantly lower HbA1c. Lipid profiles were similar between groups. CONCLUSIONS GH treatment in childhood and adolescence is associated with significantly decreased body mass index and improved body composition and metabolic status in adults with PWS at several years after discontinuing treatment.

Traditional Anthropometric Parameters Still Predict Metabolic Disorders in Women With Severe Obesity

It is well established that fat distribution rather than the total quantity of fat is the major determinant of cardiovascular risk in overweight subjects. However, it is not known whether the concept of fat distribution still makes sense in severely obese subjects. Particularly, the role of visceral fat accumulation and/or of adipocyte hypertrophy in insulin resistance (IR) has not been studied in this population. Therefore, the aim of this study was to clarify the determinants of metabolic disorders in severely obese women. We performed a cross‐sectional study in 237 severely obese women (BMI >35 kg/m2). We assessed total body fat mass and fat distribution by anthropometric measurements (BMI and waist‐to‐hip ratio (WHR)) and by dual‐energy X‐ray absorptiometry (DXA). In 22 women, we measured subcutaneous and visceral adipocyte size on surgical biopsies. Mean BMI was 44 ± 7 kg/m2 (range 35–77), mean age 37 ± 11 years (range 18–61). Lipid parameters (triglycerides, high‐density lipoprotein cholesterol) and IR markers (fasting insulin and homeostasis model assessment (HOMA) index) correlated with fat distribution, whereas inflammatory parameters (C‐reactive protein, fibrinogen) correlated only with total fat mass. An association was observed between android fat distribution and adipocyte hypertrophy. Visceral adipocyte hypertrophy was associated with both IR and hypertension, whereas subcutaneous fat‐cell size was linked only to hypertension. Our results obtained in a large cohort of women showed that fat distribution still predicts metabolic abnormalities in severe obesity. Furthermore, we found a cluster of associations among fat distribution, metabolic syndrome (MS), and adipocyte hypertrophy.

Human white and brite adipogenesis is supported by MSCA1 and is impaired by immune cells.

Obesity‐associated inflammation contributes to the development of metabolic diseases. Although brite adipocytes have been shown to ameliorate metabolic parameters in rodents, their origin and differentiation remain to be characterized in humans. Native CD45−/CD34+/CD31− cells have been previously described as human adipocyte progenitors. Using two additional cell surface markers, MSCA1 (tissue nonspecific alkaline phosphatase) and CD271 (nerve growth factor receptor), we are able to partition the CD45−/CD34+/CD31− cell population into three subsets. We establish serum‐free culture conditions without cell expansion to promote either white/brite adipogenesis using rosiglitazone, or bone morphogenetic protein 7 (BMP7), or specifically brite adipogenesis using 3‐isobuthyl‐1‐methylxanthine. We demonstrate that adipogenesis leads to an increase of MSCA1 activity, expression of white/brite adipocyte‐related genes, and mitochondriogenesis. Using pharmacological inhibition and gene silencing approaches, we show that MSCA1 activity is required for triglyceride accumulation and for the expression of white/brite‐related genes in human cells. Moreover, native immunoselected MSCA1+ cells exhibit brite precursor characteristics and the highest adipogenic potential of the three progenitor subsets. Finally, we provided evidence that MSCA1+ white/brite precursors accumulate with obesity in subcutaneous adipose tissue (sAT), and that local BMP7 and inflammation regulate brite adipogenesis by modulating MSCA1 in human sAT. The accumulation of MSCA1+ white/brite precursors in sAT with obesity may reveal a blockade of their differentiation by immune cells, suggesting that local inflammation contributes to metabolic disorders through impairment of white/brite adipogenesis. Stem Cells 2015;33:1277–1291

AZP-531, an unacylated ghrelin analog, improves food-related behavior in patients with Prader-Willi syndrome: A randomized placebo-controlled trial

Context and objective Prader-Willi syndrome (PWS) is characterized by early-onset hyperphagia and increased circulating levels of the orexigenic Acylated Ghrelin (AG) hormone with a relative deficit of Unacylated Ghrelin (UAG). AZP-531, a first-in-class UAG analog, was shown to inhibit the orexigenic effect of AG in animals, to improve glycemic control and decrease body weight in humans. We aimed to investigate the safety and efficacy of AZP-531 in patients with PWS for whom no approved treatment for hyperphagia is currently available. Methods and design Multi-center, randomized, double-blind, placebo-controlled trial. Forty-seven patients with genetically confirmed PWS and evidence of hyperphagia received daily subcutaneous injections of AZP-531 (3 and 4 mg for 50–70 kg and >70 kg body weight, respectively) or matching placebo for 14 days. Assessments included adverse events, vital signs, safety laboratory tests, the Hyperphagia Questionnaire (HQ), patient-reported appetite, body composition and glycemic measures. Results AZP-531 was well tolerated. There was a significant improvement with AZP-531 versus placebo in the mean total score, the 9-item score and the severity domain score of the HQ (p < .05). The highest reduction in the total and 9-item scores was observed in AZP-531 subjects with the highest hyperphagia score at baseline. Findings were supported by a reduction in appetite scores observed with AZP-531 only. Body weight did not change in both groups while a significant reduction in waist circumference and fat mass was observed only with AZP-531. AZP-531 significantly decreased post-prandial glucose levels in a baseline glucose dependent fashion. Conclusions AZP-531 may constitute a new treatment strategy to improve hyperphagia and metabolic issues in patients with PWS. These findings support further investigation in longer-term clinical trials.

Long-term Relapse of Type 2 Diabetes After Roux-en-Y Gastric Bypass: Prediction and Clinical Relevance

OBJECTIVE Roux-en-Y gastric bypass (RYGB) induces type 2 diabetes remission (DR) in 60% of patients at 1 year, yet long-term relapse occurs in half of these patients. Scoring methods to predict DR outcomes 1 year after surgery that include only baseline parameters cannot accurately predict 5-year DR (5y-DR). We aimed to develop a new score to better predict 5y-DR. RESEARCH DESIGN AND METHODS We retrospectively included 175 RYGB patients with type 2 diabetes with 5-year follow-up. Using machine learning algorithms, we developed a scoring method, 5-year Advanced-Diabetes Remission (5y-Ad-DiaRem), predicting longer-term DR postsurgery by integrating medical history, bioclinical data, and antidiabetic treatments. The scoring method was based on odds ratios and variables significantly different between groups. This score was further validated in three independent RYGB cohorts from three European countries. RESULTS Compared with 5y-DR patients, patients who had relapsed after 5 years exhibited more severe type 2 diabetes at baseline, lost significantly less weight during the 1st year after RYGB, and regained more weight afterward. The 5y-Ad-DiaRem includes baseline (diabetes duration, number of antidiabetic treatments, and HbA1c) and 1-year follow-up parameters (glycemia, number of antidiabetic treatments, remission status, 1st-year weight loss). The 5y-Ad-DiaRem was accurate (area under the receiver operating characteristic curve [AUROC], 90%; accuracy, 85%) at predicting 5y-DR, performed better than the Diabetes Remission score (DiaRem) and the Advanced-DiaRem (AUROC, 81% and 84%; accuracy, 79% and 78%, respectively), and correctly reclassified 13 of 39 patients misclassified with the DiaRem. The 5y-Ad-DiaRem robustness was confirmed in the independent cohorts. CONCLUSIONS The 5y-Ad-DiaRem accurately predicts 5y-DR and appears relevant to identify patients at risk for relapse. Using this score could help personalize patient care after the 1st year post-RYGB to maximize weight loss, limit weight regains, and prevent relapse.

Senescence Alters PPARγ (Peroxisome Proliferator–Activated Receptor Gamma)-Dependent Fatty Acid Handling in Human Adipose Tissue Microvascular Endothelial Cells and Favors Inflammation

Objective— Adipose tissue (AT) dysfunction associated with obesity or aging is a major cause for lipid redistribution and the progression of cardiometabolic disorders. Our goal is to decipher the contribution of human AT microvascular endothelial cells (ECs) in the maintenance of fatty acid (FA) fluxes and the impact of senescence on their function. Approach and Results— We used freshly isolated primary microvascular ECs from human AT. Our data identified the endothelial FA handling machinery including FATPs (FA transport proteins) FATP1, FATP3, FATP4, and CD36 as well as FABP4 (FA binding protein 4). We showed that PPAR&ggr; (peroxisome proliferator–activated receptor gamma) regulates the expression of FATP1, CD36, and FABP4 and is a major regulator of FA uptake in human AT EC (hATEC). We provided evidence that endothelial PPAR&ggr; activity is modulated by senescence. Indeed, the positive regulation of FA transport by PPAR&ggr; agonist was abolished, whereas the emergence of an inflammatory response was favored in senescent hATEC. This was associated with the retention of nuclear FOXO1 (forkhead box protein O1), whereas nuclear PPAR&ggr; translocation was impaired. Conclusions— These data support the notion that PPAR&ggr; is a key regulator of primary hATEC function including FA handling and inflammatory response. However, the outcome of PPAR&ggr; activation is modulated by senescence, a phenomenon that may impact the ability of hATEC to properly respond to and handle lipid fluxes. Finally, our work highlights the role of hATEC in the regulation of FA fluxes and reveals that dysfunction of these cells with accelerated aging is likely to participate to AT dysfunction and the redistribution of lipids.

Carences nutritionnelles après bypass gastrique : diagnostic, prévention et traitements

Resume Ces dernieres annees, le recours a la chirurgie de l’obesite comme traitement des obesites morbides s’est amplifie. Le nombre d’interventions de type « malabsorptives », telles que le bypass gastrique (RYGB : Roux-en-Y gastric bypass) augmente chaque annee. Le RYGB qui associe deux mecanismes favorisant la perte de poids, la restriction et la malabsorption, a prouve son efficacite en termes de perte de poids et d’amelioration des comorbidites. Cependant, cette intervention entraine une modification profonde de la physiologie digestive a l’origine de complications nutritionnelles et metaboliques. Les deficits observes les plus frequents concernent les proteines, le fer, le calcium, la vitamine B12 et la vitamine D. Les carences en vitamine B1 sont rares mais potentiellement graves. Le suivi multidisciplinaire est indispensable pour assurer le depistage, le diagnostic et la prise en charge de ces complications. Fonde sur une analyse de la litterature, cet article resume les differentes complications nutritionnelles observees apres RYGB et les moyens pour en faire le diagnostic. Il propose des recommandations pratiques de suivi, de supplementation preventive et de prise en charge des carences averees, de facon generale et dans le cas plus specifique d’une grossesse apres RYGB.