No abstract

Gut microbiota-related metabolites are potential clinical biomarkers for cardiovascular disease (CVD). Circulating succinate, a metabolite produced by both microbiota and the host, is increased in hypertension, ischemic heart disease, and type 2 diabetes. We aimed to analyze systemic levels of succinate in obesity, a major risk factor for CVD, and its relationship with gut microbiome. We explored the association of circulating succinate with specific metagenomic signatures in cross-sectional and prospective cohorts of Caucasian Spanish subjects. Obesity was associated with elevated levels of circulating succinate concomitant with impaired glucose metabolism. This increase was associated with specific changes in gut microbiota related to succinate metabolism: a higher relative abundance of succinate-producing Prevotellaceae (P) and Veillonellaceae (V), and a lower relative abundance of succinate-consuming Odoribacteraceae (O) and Clostridaceae (C) in obese individuals, with the (P + V/O + C) ratio being a main determinant of plasma succinate. Weight loss intervention decreased (P + V/O + C) ratio coincident with the reduction in circulating succinate. In the spontaneous evolution after good dietary advice, alterations in circulating succinate levels were linked to specific metagenomic signatures associated with carbohydrate metabolism and energy production with independence of body weight change. Our data support the importance of microbe–microbe interactions for the metabolite signature of gut microbiome and uncover succinate as a potential microbiota-derived metabolite related to CVD risk.

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.

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-β1 secretion, than lean-derived ASCs. Treatment of lean hASCs with interleukin (IL)-1β mimicked the dysfunctional immune behavior of obese and T2D hASCs. Conversely, combined treatment with IL1RA and TGF-β1 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.

Objective: For a long time Aquaporin-7 has been the only aquaporin associated with the adipose tissue, and its dysregulation has been linked to the underlying mechanisms of obesity. However, the presence of alternative glycerol channels within the adipose tissue has been postulated, which has prompted us to the search of alternate glycerol transport routes in adipocytes. In view of this, it is hypothesized that Aquaporin-11 (AQP11) would have a role in adipocyte cell biology. Methods: The expression, the localization and the function of human AQP11 (hAQP11) in cultured differentiated adipocytes were investigated. Results: Gene expression analysis revealed the presence of AQP11 in both subcutaneous and visceral human mature adipocytes. It is found that hAQP11 is primarily located intracellularly in human adipocytes and partially colocalizes with perilipin, pointing towards AQP11 preferential location in the vicinity of lipid droplets. Overexpression of hAQP11 in 3T3-L1 adipocytes enabled to validate its function as a water channel and reveal its glycerol permeation activity. Conclusions: hAQP11 permeates both water and glycerol, localizing in the vicinity of lipid droplets in human adipocytes.

No abstract

The present study provides evidence of a role of ZAG gene in adipose tissue metabolism, with a close association with adiponectin gene expression in sc and visceral fat.

Psoriasis has been related to metabolic syndrome (MS). Adipocytokines produced by white adipose tissue may be involved in the pathogenesis of psoriasis and its association with MS. Our objectives were to characterize the profile of a number of different inflammatory and atherogenic markers, vitamins, adipokines and cytokines and their potential involvement in MS in patients with moderate-to-severe psoriasis without joint involvement compared to anthropometrically matched controls, and to evaluate correlation with severity of the skin disease and changes after narrow-band UVB (NB-UVB) phototherapy. We designed a prospective cross-sectional study. Baseline waist circumference, body fat composition, lipid, carbohydrate and calcium metabolism profile, inflammation markers, homocysteine and vitamins D, B6, B12 and folic acid, leptin, resistin, omentin, lipocalin-2, adipocyte fatty acid-binding protein, retinol-binding protein-4 (RBP-4), interleukin-6, soluble tumour necrosis factor receptor 1 (sTNFR1) and interleukin-17 of 50 psoriasis patients and 50 gender, age and body mass index-matched controls were recorded, then evaluated after NB-UVB in the patients. The patients had higher baseline serum concentrations of leptin, RBP-4, lipocalin-2 and sTNFR1. Baseline psoriasis area and severity index correlated with serum concentrations of RBP-4 and lipocalin-2 only. Principal components analysis disclosed a component including vitamins B12, B6, folic acid, calcidiol and HDL-cholesterol that was only present in healthy controls and opposed to a cluster of variables which promote MS. This component was absent in the patients. Our results point to lipocalin-2 and RBP-4 as relevant mediators of the trend towards MS in psoriatic patients.