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Pericardial adipose tissue (PAT), a visceral fat depot enveloping the heart, is an active endocrine organ and a source of free fatty acids and inflammatory cytokines. As in other fat adult tissues, PAT contains a population of adipose stem cells; however, whether these cells and/or their environment play a role in physiopathology is unknown. We analyzed several stem cell-related properties of pericardial adipose stem cells (PSCs) isolated from obese and ex-obese mice. We also performed RNA-sequencing to profile the transcriptional landscape of PSCs isolated from the different diet regimens. Finally, we tested whether these alterations impacted on the properties of cardiac mesoangioblasts isolated from the same mice. We found functional differences between PSCs depending on their source: specifically, PSCs from obese PSC (oPSC) and ex-obese PSC (dPSC) mice showed alterations in apoptosis and migratory capacity when compared with lean, control PSCs, with increased apoptosis in oPSCs and blunted migratory capacity in oPSCs and dPSCs. This was accompanied by different gene expression profiles across the cell types, where we identified some genes altered in obese conditions, such as BMP endothelial cell precursor-derived regulator (BMPER), an important regulator of BMP-related signaling pathways for endothelial cell function. The importance of BMPER in PSCs was confirmed by loss- and gain-of-function studies. Finally, we found an altered production of BMPER and some important chemokines in cardiac mesoangioblasts in obese conditions. Our findings point to BMPER as a potential new regulator of PSC function and suggest that its dysregulation could be associated with obesity and may impact on cardiac cells. Ministerio de Ciencia e Innovación (SAF2015‐67911‐R) 6.513 JCR (2021) Q1, 10/81 Physiology 1.308 SJR (2021) Q1, 15/119 Clinical Biochemistry No data IDR 2021 UEM

Background: Lung cancer has the highest incidence and mortality rate in the world. One of the most promising new cancer therapies in recent years is immunotherapy, which is based on the blockade of immune checkpoints such as programmed cell death protein 1 (PD-1). Exercise training is beneficial to maintain and improve the quality of life of cancer patients, and it might also modulate the anti-tumoral efficiency of some chemotherapeutic agents. However, the potential of exercise combined with immunotherapy as a cancer therapy remains to be elucidated. Here, we examined the effects of exercise on tumor growth and its possible adjuvant effects when combined with anti-PD-1 immunotherapy (nivolumab) in a patient derived xenograft (PDX) model of non-small-cell lung carcinoma (NSCLC). Methods: We generated a PDX model using NOD-SCID gamma mice with subcutaneous grafts from tumor tissue of a patient with NSCLC. Animals were randomly assigned to one of four groups: non-exercise + isotype control (n=5), exercise + isotype control (n=5), non-exercise + nivolumab (n=6) or exercise + nivolumab (n=6). The animals undertook an 8- week moderate-intensity training regimen (treadmill aerobic exercise and strength training). Immunotherapy (nivolumab) or an isotype control was administered 2 days/week, for 6 weeks. Several tumor growth and microenvironment parameters were measured after the intervention. Results: Improvements in aerobic capacity and muscle strength (p=0.027 and p=0.005) were noted in exercised animals. Exercise alone reduced the tumor growth rate with respect to non-exercised mice (p=0.050). The double intervention (exercise + nivolumab) increased tumor necrosis and reduced apoptosis with respect to controls (p=0.026; p=0.030). All interventions achieved a reduction in proliferation compared with the control group (p=0.015, p=0.011, and p=0.011). Exercise alone increased myeloid tumor infiltrates (mostly neutrophils) with respect to the nivolumab only group (p=0.018). Finally, Vegf-a expression was higher in the nivolumab groups (in combination or not with exercise) than in exercise + isotype control group (p=0.045 and p=0.047, respectively). No other significant effects were found. Conclusions: Our results would suggest that aerobic and strength training should be studied as an adjuvant to cancer immunotherapy treatment. Spanish Ministry of Economy and Competitiveness and Fondos FEDER - Fondo de Investigaciones Sanitarias (PI15/00558, PI18/00139 & PIE14/0064) 6.308 JCR (2020) Q1, 40/162 Inmunology 1.557 SJR (2020) Q1, 21/125 Sports Science No data IDR 2019 UEM

Sin financiación No data (2016) UEM

The increasing aging of our societies is accompanied by a pandemic of obesity and related cardiometabolic disorders. Progressive dysfunction of the white adipose tissue is increasingly recognized as an important hallmark of the aging process which in turn contributes to metabolic alterations, multi-organ damage, and a systemic pro-inflammatory state ('inflammaging'). On the other hand, obesity, the paradigm of adipose tissue dysfunction, shares numerous biological similarities with the normal aging process such as chronic inflammation and multi-system alterations. Accordingly, understanding the interplay between accelerated aging related to obesity and adipose tissue dysfunction is critical to gain insight into the aging process in general as well as into the pathophysiology of obesity and other related conditions. Here we postulate the concept of 'adipaging' to illustrate the common links between aging and obesity and the fact that, to a great extent, obese adults are prematurely aged individuals. SAF 2010-15239 SAF2015-67911 4.739 JCR (2016) Q1, 9/84 Physiology, 50/259 Neurosciences 2.192 SJR (2016) Q1, 22/191 Physiology, 7/127 Sports Science No data IDR 2016 UEM

The therapeutic potential of adipose-derived stem cells (ASCs) is reduced by various stress-inducing conditions that affect tissue homeostasis such as diabetes, aging, and obesity. Previous works have provided evidence of negative effects of obesity on ASC populations, but it is unclear whether this persists after a weight loss. This study evaluated whether weight loss can restore the attenuated properties found in ASCs derived from populations with obesity (oASCs). SAF 2010-15239 3.873 JCR (2016) Q1, 18/81 Nutrition and Dietetics; Q2, 39/138 Endocrinology and Metabolism UEM

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 30-04-2015

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 17-11-2014, Adipose tissue is a major source of stem cells (ASC). This subtype of stem cells exhibits properties typical of the mesenchymal stem cells (MSC): they are pluripotent and self-renewal, but also they are easy to isolate. However, in this study it has been shown that the environment where the stem cells reside can lead to morphological and functional changes, disturbing the main properties of these cells. Obese ASCs have an increased production of different inflammatory factors, so the cells are in a high inflammatory environment. It has been observed that obese ASCs maintain the ability to differentiate into other tissues, but have an impaired ability to form functional adipocytes, and they present an insulin-resistant phenotype. We have shown that the regenerative capacity of these cells is also affected by obesity. Obese ASCs have reduced ability to proliferate, migrate and form tubular structures, so then they are less capable of reaching and repairing the target when they are used in cell therapy. It has been found that in obese conditions ASCs have an increased mitochondria number associated with an increase in ROS production during cell culture. Furthermore, it has been observed that mitochondria from obese ASCs are able to use better fatty acids than glucose as carbon source in the respiration process than nonobese ASCs. Moreover, obesity induces genetic instability, since the increase of ROS has associated a telomere shortening and a change in the DNA hydroxymethylation state as well as changes in p21 and p53 expression levels. These changes can explain the reduction of self-renewal and multipotency capacities in obese ASCs. Finally, high levels of glucose in the medium and a decrease in the glucose uptake confirm that obese ASCs have an insulin-resistant phenotype. Obesity is a condition that leads to metabolic dysfunction in the subject, and this dysfunction is acquired by the stem cells from adipose tissue. Therefore, the functionality of stem cells for their use in cell therapy is diminished, and it is necessary to increase controls applied in the selection of cells for use in cellular therapies.