ABHD6 suppression promotes anti-inflammatory polarization of adipose tissue macrophages via 2-monoacylglycerol/PPAR signaling in obese mice

Objective: Pro-inflammatory polarization of adipose tissue macrophages (ATMs) plays a critical role in the pathogenesis of obesity-associated chronic inflammation. However, little is known about the role of lipids in the regulation of ATMs polarity and inflammation in response to metabolic stress. Deletion of α/β-hydrolase domain-containing 6 (ABHD6), a monoacylglycerol (MAG) hydrolase, has been shown to protect against diet-induced obesity and insulin resistance. Methods: Here we investigated the immunometabolic role of macrophage ABHD6 in response to nutrient excess using whole-body ABHD6-KO mice and human and murine macrophage cell-lines treated with KT203, a selective and potent pharmacological ABHD6 inhibitor. Results: KO mice on high-fat diet showed lower susceptibility to systemic diet-induced inflammation. Moreover, in the setting of overnutrition, stromal vascular cells from gonadal fat of KO vs. control mice contained lower number of M1 macrophages and exhibited enhanced levels of metabolically activated macrophages (MMe) and M2 markers, oxygen consumption, and interleukin-6 (IL-6) release. Likewise, under in vitro nutri-stress condition, inhibition of ABHD6 in MMe-polarized macrophages attenuated the expression and release of pro-inflammatory cytokines and M1 markers and induced the upregulation of lipid metabolism genes. ABHD6-inhibited MMe macrophages showed elevated levels of peroxisome proliferator-activated receptors (PPARs) and 2-MAG species. Notably, among different MAG species, only 2-MAG treatment led to increased levels of PPAR target genes in MMe macrophages. Conclusions: Collectively, our findings identify ABHD6 as a key component of pro-inflammatory macrophage activation in response to excess nutrition and implicate an endogenous macrophage lipolysis/ABHD6/2-MAG/PPARs cascade, as a lipid signaling and immunometabolic pathway, which favors the anti-inflammatory polarization of ATMs in obesity

Colorectal Endoscopic Stenting Trial (CReST) for obstructing left-sided colorectal cancer: randomized clinical trial

Background Colorectal cancer often presents with obstruction needing urgent, potentially life-saving decompression. The comparative efficacy and safety of endoluminal stenting versus emergency surgery as initial treatment for such patients is uncertain. Methods Patients with left-sided colonic obstruction and radiological features of carcinoma were randomized to endoluminal stenting using a combined endoscopic/fluoroscopic technique followed by elective surgery 1–4 weeks later, or surgical decompression with or without tumour resection. Treatment allocation was via a central randomization service using a minimization procedure stratified by curative intent, primary tumour site, and severity score (Acute Physiology And Chronic Health Evaluation). Co-primary outcome measures were duration of hospital stay and 30-day mortality. Secondary outcomes were stoma formation, stenting completion and complication rates, perioperative morbidity, 6-month survival, 3-year recurrence, resource use, adherence to chemotherapy, and quality of life. Analyses were undertaken by intention to treat. Results Between 23 April 2009 and 22 December 2014, 245 patients from 39 hospitals were randomized. Stenting was attempted in 119 of 123 allocated patients (96.7 per cent), achieving relief of obstruction in 98 of 119 (82.4 per cent). For the 89 per cent treated with curative intent, there were no significant differences in 30-day postoperative mortality (3.6 per cent (4 of 110) versus 5.6 per cent (6 of 107); P = 0.48), or duration of hospital stay (median 19 (i.q.r. 11–34) versus 18 (10–28) days; P = 0.94) between stenting followed by delayed elective surgery and emergency surgery. Among patients undergoing potentially curative treatment, stoma formation occurred less frequently in those allocated to stenting than those allocated to immediate surgery (47 of 99 (47.5 per cent) versus 72 of 106 (67.9 per cent); P = 0.003). There were no significant differences in perioperative morbidity, critical care use, quality of life, 3-year recurrence or mortality between treatment groups. Conclusion Stenting as a bridge to surgery reduces stoma formation without detrimental effects. Registration number: ISRCTN13846816 (http://www.controlled-trials.com)