Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis

Objective: Obesity is associated with metabolic dysfunction of white adipose tissue (WAT). Activated adipocytes secrete pro-inflammatory cytokines resulting in the recruitment of pro-inflammatory macrophages, which contribute to WAT insulin resistance. The bile acid (BA)-activated nuclear Farnesoid X Receptor (FXR) controls systemic glucose and lipid metabolism. Here, we studied the role of FXR in adipose tissue function. Methods: We first investigated the immune phenotype of epididymal WAT (eWAT) from high fat diet (HFD)-fed whole-body FXR-deficient (FXR−/−) mice by flow cytometry and gene expression analysis. We then generated adipocyte-specific FXR-deficient (Ad-FXR−/−) mice and analyzed systemic and eWAT metabolism and immune phenotype upon HFD feeding. Transcriptomic analysis was done on mature eWAT adipocytes from HFD-fed Ad-FXR−/− mice. Results: eWAT from HFD-fed whole-body FXR−/− and Ad-FXR−/− mice displayed decreased pro-inflammatory macrophage infiltration and inflammation. Ad-FXR−/− mice showed lower blood glucose concentrations, improved systemic glucose tolerance and WAT insulin sensitivity and oxidative stress. Transcriptomic analysis identified Gsta4, a modulator of oxidative stress in WAT, as the most upregulated gene in Ad-FXR−/− mouse adipocytes. Finally, chromatin immunoprecipitation analysis showed that FXR binds the Gsta4 gene promoter. Conclusions: These results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis

Combining Postcards, Crisis Cards, and Telephone Contact Into a Decision-Making Algorithm to Reduce Suicide Reattempt

International audienceBACKGROUND:There is growing evidence in the literature that brief contact interventions (BCIs) might be reliable suicide prevention strategies.OBJECTIVE:To assess the effectiveness of a decision-making algorithm for suicide prevention (ALGOS) combining existing BCIs in reducing suicide reattempts in patients discharged after a suicide attempt.METHODS:A randomized, multicenter, controlled, parallel trial was conducted in 23 hospitals. The study was conducted from January 26, 2010, to February 28, 2013. People who had made a suicide attempt were randomly assigned to either the intervention group (ALGOS) or the control group. The primary outcome was the rate of participants who reattempted suicide (fatal or not) within the 6-month study period.RESULTS:1,040 patients were recruited. After 6 months, 58 participants in the intervention group (12.8%) reattempted suicide compared with 77 (17.2%) in the control group. The difference between groups (4.4%; 95% CI, -0.7% to 9.0%) was not significant (complete-case analysis, P = .059).CONCLUSIONS:These results may help researchers better integrate BCIs into routine health care and provide new insights concerning personalized suicide prevention strategies.TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01123174

Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells.

Bile acids are signalling molecules, which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex bile acids in the intestinal lumen and decrease intestinal FXR activity. The BAS-BA complex also induces glucagon-like peptide-1 (GLP-1) production by L cells which potentiates β-cell glucose-induced insulin secretion. Whether FXR is expressed in L cells and controls GLP-1 production is unknown. Here, we show that FXR activation in L cells decreases proglucagon expression by interfering with the glucose-responsive factor Carbohydrate-Responsive Element Binding Protein (ChREBP) and GLP-1 secretion by inhibiting glycolysis. In vivo, FXR deficiency increases GLP-1 gene expression and secretion in response to glucose hence improving glucose metabolism. Moreover, treatment of ob/ob mice with the BAS colesevelam increases intestinal proglucagon gene expression and improves glycaemia in a FXR-dependent manner. These findings identify the FXR/GLP-1 pathway as a new mechanism of BA control of glucose metabolism and a pharmacological target for type 2 diabetes

Simple Aspiration versus Drainage for Complete Pneumothorax: A Randomized Noninferiority Trial

International audienceRationale: Management of first episodes of primary spontaneous pneumothorax remains the subject of debate.Objectives: To determine whether first-line simple aspiration is noninferior to first-line chest tube drainage for lung expansion in patients with complete primary spontaneous pneumothorax.Methods: We conducted a prospective, open-label, randomized noninferiority trial. Adults aged 18–50 years with complete primary spontaneous pneumothorax (total separation of the lung from the chest wall), recruited at 31 French hospitals from 2009 to 2015, received simple aspiration (n = 200) or chest tube drainage (n = 202) as first-line treatment. The primary outcome was pulmonary expansion 24 hours after the procedure. Secondary outcomes were tolerance of treatment, occurrence of adverse events, and recurrence of pneumothorax within 1 year. Substantial discordance in the numerical inputs used for trial planning and the actual trial rates of the primary outcome resulted in a reevaluation of the trial analysis plan.Measurement and Main Results: Treatment failure occurred in 29% in the aspiration group and 18% in the chest tube drainage group (difference in failure rate, 0.113; 95% confidence interval [CI], 0.026–0.200). The aspiration group experienced less pain overall (mean difference, −1.4; 95% CI, −1.89, −0.91), less pain limiting breathing (frequency difference, −0.18; 95% CI, −0.27, −0.09), and less kinking of the device (frequency difference, −0.05; 95% CI, −0.09, −0.01). Recurrence of pneumothorax was 20% in this group versus 27% in the drainage group (frequency difference, −0.07; 95% CI, −0.16, +0.02).Conclusions: First-line management of complete primary spontaneous pneumothorax with simple aspiration had a higher failure rate than chest tube drainage but was better tolerated with fewer adverse events