Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance.

Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes.

Decision Tree for the Performance of Intraoperative Liver Biopsy During Bariatric Surgery.

BACKGROUND AND AIMS: Bariatric surgery provides a useful opportunity to perform intraoperative liver biopsy to screen for non-alcoholic steatohepatitis (NASH). There is currently no consensus on whether intraoperative liver biopsy should be systematically performed. The aim of this study was to develop and validate a decision tree to guide that choice. APPROACH AND RESULTS: This prospective study included 102 consecutive patients from the severe obesity outcome network (SOON) cohort in whom liver biopsy was systematically performed during bariatric surgery. A classification and regression tree (CART) was created to identify the nodes that best classified patients with and without NASH. External validation was performed. Seventy-one biopsies were of sufficient quality for analysis (median body mass index 43.3 [40.7; 48.0] kg/m2). NASH was diagnosed in 32.4% of cases. None of the patients with no steatosis on ultrasound had NASH. The only CART node that differentiated between a "high-risk" and a "low-risk" of NASH was alanine aminotransferase (ALT). ALT>53IU/L predicted NASH with a positive predictive value (PPV) of 68% and a negative predictive value (NPP) of 89%, a sensitivity of 77%, and a specificity of 84%. In the external cohort (n=258), PPV was 68%, NPV was 62%, sensitivity was 27%, and specificity was 90%. CONCLUSIONS: The present work supports intraoperative liver biopsy to screen for NASH in patients with ALT>53IU/L; however, patients with no steatosis on ultrasound should not undergo biopsy. The CART failed to identify an algorithm with a good sensitivity to screen for NASH in patients with ultrasonography-proven steatosis and ALT≤53IU/L.

Decision-making in obesity without eating disorders: a systematic review and meta-analysis of Iowa gambling task performances.

BACKGROUND: There is evidence that obesity is associated with impairments in executive functions, such as deficits in decision-making, planning or problem solving, which might interfere with weight loss in obese individuals. We performed a systematic review and meta-analysis of decision-making abilities, as measured with the Iowa gambling task (IGT), in obesity without eating disorders. METHODS: A systematic search was conducted to identify studies comparing IGT performances between groups of obese patients without eating disorders and groups of healthy control groups. The standardized mean differences were calculated for the total IGT scores and for the course of IGT scores. Meta-regression analyses were performed to explore the influence of clinical variables on standardized mean differences. RESULTS: Total IGT scores were significantly lower in obese patients compared with normal-weight healthy controls. IGT performances did not differ between groups for the first trials of the task. Significant effect sizes for the last trials of the task were subjected to a high degree of heterogeneity. CONCLUSION: Risky decision-making is impaired in obesity. The clinical importance of non-food-related decision-making impairments remains to be assessed especially in terms of consequences in daily life or the achievement of weight loss. This meta-analysis has been registered in the Prospero database (CRD42016037533).

Serum lipidomics reveals early differential effects of gastric bypass compared with banding on phospholipids and sphingolipids independent of differences in weight loss.

BACKGROUND/OBJECTIVES: Circulating phospholipids and sphingolipids are implicated in obesity-related comorbidities such as insulin resistance and cardiovascular disease. How bariatric surgery affects these important lipid markers is poorly understood. We sought to determine whether Roux-en-Y gastric bypass (RYGB), which is associated with greater metabolic improvement, differentially affects the phosphosphingolipidome compared with adjustable gastric banding (AGB). SUBJECTS/METHODS: Fasting sera were available from 59 obese women (body mass index range 37-51 kg m-2; n=37 RYGB and 22 AGB) before surgery, then at 1 (21 RYGB, 12 AGB) and 3 months follow-up (19 RYGB, 12 AGB). HPLC-MS/MS was used to quantify 131 lipids from nine structural classes. DXA measurements and laboratory parameters were also obtained. The associations between lipids and clinical measurements were studied with P-values adjusted for the false discovery rate (FDR). RESULTS: Both surgical procedures rapidly induced weight loss and improved clinical profiles, with RYGB producing better improvements in fat mass, and serum total cholesterol, low-density lipoprotein-cholesterol (LDL-C) and orosomucoid (FDR <10%). Ninety-three (of 131) lipids were altered by surgery-the majority decreasing-with 29 lipids differentially affected by RYGB during the study period. The differential effect of the surgeries remained statistically significant for 20 of these lipids after adjusting for differences in weight loss between surgery types. The RYGB signature consisted of phosphatidylcholine species not exceeding 36 carbons, and ceramides and sphingomyelins containing C22 to C25 fatty acids. RYGB also led to a sustained increase in unsaturated ceramide and sphingomyelin species. The RYGB-specific lipid changes were associated with decreases in body weight, total and LDL-C, orosomucoid and increased HOMA-S (FDR <10%). CONCLUSIONS: Concomitant with greater metabolic improvement, RYGB induced early and sustained changes in phosphatidylcholines, sphingomyelins and ceramides that were independent of greater weight loss. These data suggest that RYGB may specifically alter sphingolipid metabolism, which, in part, could explain the better metabolic outcomes of this surgical procedure.

[Bariatric surgery in obese adolescents: When and how should the transition from pediatric to adult medical management be made?]. / Prise en charge médico-chirurgicale de l'obésité de l'adolescent : quand et comment réaliser la transition vers la prise en charge adulte ?

INTRODUCTION: In young obese patients, the transition from adolescence to adulthood, i.e., the transition from the pediatric to the adult medical team, is a new issue. In particular, it is important to define when and how this transition should be made in the setting of bariatric surgery. MATERIALS AND METHODS: Fourteen young obese patients (under the age of 20), who underwent bariatric surgery, were included in the study (nine cases of Roux-en-Y gastric by-pass, three sleeve gastrectomy, one gastric banding). After surgery, the patients were followed in both the pediatric and adult departments (protocol 1) or only in the pediatric department during the 1st year and then in the adult department afterwards (protocol 2). Anthropometric and metabolic data, before and after surgery, and compliance monitoring were analyzed using a retrospective design. Twelve patients completed a questionnaire assessing how they experienced the transition. RESULTS: Before surgery, mean age±SD was 16.3±1.8 years old and mean body mass index (BMI) 55.0±8.6kg/m(2). At 1 year after surgery, mean weight loss was -32.1±8.2% of initial body weight. Adherence to vitamin supplementation was judged to be adequate (vitamins were not taken less than once a week) for only 57.5% patients. Mean follow-up was 34.8±25.1 months [95% CI, 9.5-78.4]. None of the patients was lost to follow-up. Compliance was significantly better for patients following protocol 2. Adolescents reported being satisfied with meetings and newsletters about surgery, specific to this age group (91.7%). They also reported that information on the adult department was sufficient and 91.7% of them expressed satisfaction on the first outpatient visit in the adult department. However, all patients spontaneously reported having difficulties identifying members of the different teams: nutritionist pediatrician, nutritionist, and adult surgeon. DISCUSSION: These preliminary data suggest that, in obese adolescents, it is important to differentiate the transition period and the time and preparation for bariatric surgery. A prospective follow-up with a larger number of subjects and recommendations are needed to better define and improve the specific clinical management of obese adolescents transitioning to adulthood.

Gut microbiota and non-alcoholic fatty liver disease: new insights.

Non-alcoholic fatty liver disease (NAFLD) is a severe liver disease that is increasing in prevalence with the worldwide epidemic of obesity and its related insulin-resistance state. A 'two-hit' mechanism has been proposed; however, the complete physiopathogenesis remains incompletely understood. Evidence for the role of the gut microbiota in energy storage and the subsequent development of obesity and some of its related diseases is now well established. More recently, a new role of gut microbiota has emerged in NAFLD. The gut microbiota is involved in gut permeability, low-grade inflammation and immune balance, it modulates dietary choline metabolism, regulates bile acid metabolism and produces endogenous ethanol. All of these factors are molecular mechanisms by which the microbiota can induce NAFLD or its progression toward overt non-alcoholic steatohepatitis.