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Adipose tissue is a multifunctional organ that regulates many physiological processes such as energy homeostasis, nutrition, the regulation of insulin sensitivity, body temperature, and immune response. In this review, we highlight the relevance of the different mediators that control adipose tissue activity through a systematic review of the main players present in white and brown adipose tissues. Among them, inflammatory mediators secreted by the adipose tissue, such as classical adipokines and more recent ones, elements of the immune system infiltrated into the adipose tissue (certain cell types and interleukins), as well as the role of intestinal microbiota and derived metabolites, have been reviewed. Furthermore, anti-obesity mediators that promote the activation of beige adipose tissue, e.g., myokines, thyroid hormones, amino acids, and both long and micro RNAs, are exhaustively examined. Finally, we also analyze therapeutic strategies based on those mediators that have been described to date. In conclusion, novel regulators of obesity, such as microRNAs or microbiota, are being characterized and are promising tools to treat obesity in the future.

Obesity affects the functional capability of adipose-derived stem cells (ASCs) and their effective use in regenerative medicine through mechanisms that are still poorly understood. In the present study we used a multiplatform [LC/MS, GC/MS and capillary electrophoresis/MS (CE/MS)], metabolomics, untargeted approach to investigate the metabolic alteration underlying the inequalities observed in obesity-derived ASCs. The metabolic fingerprint (metabolites within the cells) and footprint (metabolites secreted in the culture medium), from obesity- and non-obesity-derived ASCs of humans or mice, were characterized to provide valuable information. Metabolites associated with glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and the polyol pathway were increased in the footprint of obesity-derived human ASCs, indicating alterations in carbohydrate metabolism, whereas, from the murine model, deep differences in lipid and amino acid catabolism were highlighted. Therefore, new insights on the ASCs' metabolome were provided that enhance our understanding of the processes underlying ASCs' stemness capacity and its relationship with obesity, in different cell models., (© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.)

The increasing ageing 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 ageing process, which in turn contributes to metabolic alterations, multi-organ damage and a systemic pro-inflammatory state ('inflammageing'). On the other hand, obesity, the paradigm of adipose tissue dysfunction, shares numerous biological similarities with the normal ageing process such as chronic inflammation and multi-system alterations. Accordingly, understanding the interplay between accelerated ageing related to obesity and adipose tissue dysfunction is critical to gain insight into the ageing 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 ageing and obesity and the fact that, to a great extent, obese adults are prematurely aged individuals., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Inflammation is a double-edged sword with both detrimental and beneficial consequences. Understanding of the mechanisms of crosstalk between the inflammatory milieu and human adult mesenchymal stem cells is an important basis for clinical efforts. Here, we investigate changes in the transcriptional response of human adipose-derived stem cells to physiologically relevant levels of IL-2 (IL-2 priming) upon replicative senescence. Our data suggest that replicative senescence might dramatically impede human mesenchymal stem cell (MSC) function via global transcriptional deregulation in response to IL-2. We uncovered a novel senescence-associated transcriptional signature in human adipose-derived MSCs hADSCs after exposure to pro-inflammatory environment: significant enhancement of the expression of the genes encoding potent growth factors and cytokines with anti-inflammatory and migration-promoting properties, as well as genes encoding angiogenic and anti-apoptotic promoting factors, all of which could participate in the establishment of a unique microenvironment. We observed transcriptional up-regulation of critical components of the nitric oxide synthase pathway (iNOS) in hADSCs upon replicative senescence suggesting, that senescent stem cells can acquire metastasis-promoting properties via stem cell-mediated immunosuppression. Our study highlights the importance of age as a factor when designing cell-based or pharmacological therapies for older patients and predicts measurable biomarkers characteristic of an environment that is conducive to cancer cells invasiveness and metastasis.

Adipose stem cells (ASCs) are an appealing source of cells for therapeutic intervention; however, the environment from which ASCs are isolated may impact their usefulness. Using a range of functional assays, we have evaluated whether ASCs isolated from an obese environment are comparable to cells from non-obese adipose tissue. Results showed that ASCs isolated from obese tissue have a reduced proliferative ability and a loss of viability together with changes in telomerase activity and DNA telomere length, suggesting a decreased self-renewal capacity. Metabolic analysis demonstrated that mitochondrial content and function was impaired in obese-derived ASCs resulting in changes in favored oxidative substrates. These findings highlight the impact of obesity on adult stem properties. Hence, caution should be exercised when considering the source of ASCs for cellular therapies since their therapeutic potential may be impaired.

Efficient delivery of stem cells to target tissues is a major problem in regenerative medicine. Adipose derived stem cells have been proposed as important tools in cell therapy for recovering tissues after damage. Nevertheless, the ability of these ASCs to migrate or invade in order to reach the tissue of interest has not been tested so far. In this study we present evidence that the ASCs derived from obese subjects present a detrimental ability to migrate and invade in comparison with ASCs derived from control subjects. Besides, obese-derived ASCs are unable to respond to certain stimuli and to form enough capillaries after stimulation. We propose that the use of specific cytokines could overcome these deficiencies of the obese environment, offering a tool to optimize cell therapy.

Most adult tissues harbour a stem cell subpopulation (Mesenchymal Precursors or MPs) that represent a small proportion of the total cell number and have the potential to differentiate into several cell types within the mesenchymal lineage. In adipose tissue, adipocytes account for two-thirds of the total cell number. The remaining cells include blood and endothelial cells, along with adipocyte precursors (adipose MPs). Obesity is defined as an excess of body fat that frequently results in a significant impairment of health. The ob/ob mice bear a mutation in the ob gene that causes a deficiency in the hormone leptin and hence obesity. Here, we present evidence that ob/ob mice have a dramatic decrease in the resident MP pool of several tissues, including squeletal muscle, heart, lung and adipose tissue. Moreover, we show that that there is a migration of MP cells from distant organs, as well as homing of these cells to the adipose tissue mass of the ob/ob mice. We call this process adipotaxis. Once in the adipose tissue, migrant MPs undergoe adipose differentiation, giving rise to new differentiated adipocytes within the adipose mass. Finally, we provide evidence that adipotaxis is largely explained by the production of high levels of Tumor Necrosis Factor-alpha (TNF-alpha) within the ob/ob adipose tissue. The therapeutic implications for human obesity as well as for regenerative medicine are further discussed in this paper.