SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity.

Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate-SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation.

Angiopoietin-like protein 8/betatrophin as a new determinant of type 2 diabetes remission after bariatric surgery.

This work aimed to explore the link between angiopoietin-like protein 8 (ANGPTL8) and weight loss after metabolic surgery. In the cross-sectional study (n = 100), circulating ANGPTL8 concentrations were significantly lower in morbidly obese than in lean subjects, and strikingly lower in morbidly obese patients with type 2 diabetes mellitus (T2DM). Conversely, ANGPTL8 expression in subcutaneous adipose tissue (SAT) was higher in morbidly obese patients, particularly in those with T2DM, whereas its expression in visceral adipose tissue was unchanged. The main predictors for circulating levels of ANGPTL8 were BMI and T2DM, whereas ANGPTL8 expression in SAT was determined by the presence of T2DM. The prospective cohort studies before and 1 year after bariatric surgery in morbidly obese patients with (n = 45) and without (n = 30) T2DM, revealed a significant increase of circulating ANGPTL8 levels 1 year after the bariatric surgery. Intriguingly, this increment, which was predicted by basal ANGPTL8 concentrations, appeared as a determinant of T2DM remission. In conclusion, circulating ANGPTL8 levels have an inverse relationship with SAT expression. Low basal levels of ANGPTL8 rebound after bariatric surgery. The increment in ANGPTL8 concentrations at 1 month of follow-up after weight loss emerged as a significant predictor of the T2DM remission at 1 year of follow-up.

Obesity and Type 2 Diabetes Alters the Immune Properties of Human Adipose Derived Stem Cells.

Adipose tissue-derived stem cells (ASCs) are proposed as an alternative stem cell source to bone marrow-derived cells for immune cell therapy. However, microenvironmental factors may impact the functionality of this population in human adipose tissue (AT). We hypothesized that the fat depot in addition to the donor phenotype controls the immunomodulatory capacity of ASCs. Focusing on obesity and type 2 diabetes (T2D) as metabolic disorders that might affect the immune response of ASCs, we compared the inflammatory response of ASCs from subcutaneous and visceral AT of age-matched donors (lean n = 4, body mass index [BMI] 21.98 ± 1.9; obese n = 4 BMI 33.1 ± 2.1 and T2D n = 4 BMI 35.3 ± 1.5). Obese and particularly T2D-derived ASCs showed increased expression of inflammatory markers, activation of NLRP3 inflammasome and higher migration, invasion and phagocytosis capacities than those derived from lean donors. Remarkably, ASCs derived from obese and T2D subjects exhibited a reduction in typical immunosuppressive activities attributed to stem cells. Accordingly, obese and T2D-ASCs were less effective in suppressing lymphocyte proliferation, activating the M2 macrophage phenotype, and in increasing TGF-ß1 secretion, than lean-derived ASCs. Treatment of lean hASCs with interleukin (IL)-1ß mimicked the dysfunctional immune behavior of obese and T2D hASCs. Conversely, combined treatment with IL1RA and TGF-ß1 reverted the phenotype of obese- and T2D-ASCs. These data indicate that the donor metabolic phenotype compromises the immunomodulatory properties of ASCs. These results are relevant not only for understanding the physiology of ASCs in terms of cell-based therapies but also for their role as key regulators of the immune response. Stem Cells 2016;34:2559-2573.

[Long-term results of emergency surgery for colon cancer compared with elective surgery]. / Resultados a largo plazo de la cirugía urgente y electiva del cáncer de colon. Estudio comparativo.

INTRODUCTION: Currently, the mechanisms that worsen the prognosis of complicated colon cancers are still not well known. Moreover, the possible effect of using sound oncological principles in emergency surgery on long-term prognosis has not been studied in detail. AIMS: The aim of the present study was to analyze the 5-year efficacy of curative oncological surgery for complicated colon cancer performed in an emergency setting in terms of tumor recurrence and survival compared with elective surgery of uncomplicated tumors. PATIENTS AND METHOD: We performed a prospective observational cohort study in patients who underwent emergency surgery for complicated colon cancer (group 1) and patients who underwent elective surgery (group 2). Exclusion criteria were tumors of less than 15 cm from the anal verge, palliative surgery, and distant metastases. RESULTS: During the study period, 646 patients underwent surgery: there were 165 (25.5%) emergency surgeries and 481 (74.5%) elective interventions. Surgery was considered curative in 456 (70.6%) patients: 102 (22.4%) emergency and 354 (77.6%) elective surgeries. Significant differences were found in disease stage between the 2 groups (P = 0.003). The postoperative mortality rate was 12.7% in group 1 and 3.4% in group 2 (P = 0.001). When patients were stratified by TNM stage, worse 5-year cancer-related and disease-free survival rates were observed in group 1 patients with stage II tumors. No differences were found in cancer-related survival rates in stage III patients (P = 0.178). There were no significant differences in overall survival, cancer-related survival or tumor recurrence rates when group 1 was compared with a subgroup of patients in group 2 with factors of poor prognosis. CONCLUSIONS: Complicated colon cancer presents in more advanced stages and had a worse overall long-term prognosis than uncomplicated tumour. These differences decrease when patients are subclassified by tumoral stage. Overall survival and cancer-related survival rates similar to those of elective surgery can be achieved in emergency surgery when curative oncological resection is performed.