Adipokines in obesity and metabolic-related-diseases.

The discovery of leptin in the 1990s led to a reconsideration of adipose tissue (AT) as not only a fatty acid storage organ, but also a proper endocrine tissue. AT is indeed capable of secreting bioactive molecules called adipokines for white AT or batokines for brown/beige AT, which allow communication with numerous organs, especially brain, heart, liver, pancreas, and/or the vascular system. Adipokines exert pro or anti-inflammatory activities. An equilibrated balance between these two sets ensures homeostasis of numerous tissues and organs. During the development of obesity, AT remodelling leads to an alteration of its endocrine activity, with increased secretion of pro-inflammatory adipokines relative to the anti-inflammatory ones, as shown in the graphical abstract. Pro-inflammatory adipokines take part in the initiation of local and systemic inflammation during obesity and contribute to comorbidities associated to obesity, as detailed in the present review.

Pathogenic Role of Adipose Tissue-Derived Mesenchymal Stem Cells in Obesity and Obesity-Related Inflammatory Diseases.

Adipose tissue-derived mesenchymal stem cells (ASCs) are adult stem cells, endowed with self-renewal, multipotent capacities, and immunomodulatory properties, as mesenchymal stem cells (MSCs) from other origins. However, in a pathological context, ASCs like MSCs can exhibit pro-inflammatory properties and attract inflammatory immune cells at their neighborhood. Subsequently, this creates an inflammatory microenvironment leading to ASCs' or MSCs' dysfunctions. One such example is given by obesity where adipogenesis is impaired and insulin resistance is initiated. These opposite properties have led to the classification of MSCs into two categories defined as pro-inflammatory ASC1 or anti-inflammatory ASC2, in which plasticity depends on the micro-environmental stimuli. The aim of this review is to (i) highlight the pathogenic role of ASCs during obesity and obesity-related inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, and cancer; and (ii) describe some of the mechanisms leading to ASCs dysfunctions. Thus, the role of soluble factors, adhesion molecules; TLRs, Th17, and Th22 cells; γδ T cells; and immune checkpoint overexpression will be addressed.

Adipose-Tissue-Derived Mesenchymal Stem Cells Mediate PD-L1 Overexpression in the White Adipose Tissue of Obese Individuals, Resulting in T Cell Dysfunction.

The PD-L1/PD-1 immune checkpoint axis is the strongest T cell exhaustion inducer. As immune dysfunction occurs during obesity, we analyzed the impact of obesity on PD-L1/PD-1 expression in white adipose tissue (WAT) in mice and in human white adipocytes. We found that PD-L1 was overexpressed in WAT of diet-induced obese mice and was associated with increased expression of PD-1 in visceral but not subcutaneous WAT. Human in vitro cocultures with adipose-tissue-derived mesenchymal stem cells (ASC) and mononuclear cells demonstrated that the presence of ASC harvested from obese WAT (i) enhanced PD-L1 expression as compared with ASC from lean WAT, (ii) decreased Th1 cell cytokine secretion, and (iii) resulted in decreased cytolytic activity towards adipocytes. Moreover, (iv) the implication of PD-L1 in obese ASC-mediated T cell dysfunction was demonstrated through PD-L1 blockade. Finally, (v) conditioned media gathered from these cocultures enhanced PD-L1 expression in freshly differentiated adipocytes, depending on IFNγ. Altogether, our results suggest that PD-L1 is overexpressed in the WAT of obese individuals during IFNγ secretion, leading to T cell dysfunction and notably reduced cytolytic activity. Such a mechanism could shed light on why adipose-tissue-infiltrating viruses, such as SARS-CoV-2, can worsen disease in obese individuals.

Involvement of glycated albumin in adipose-derived-stem cell-mediated interleukin 17 secreting T helper cell activation.

BACKGROUND: Advanced glycation end products (AGE) are a marker of various diseases including diabetes, in which they participate to vascular damages such as retinopathy, nephropathy and coronaropathy. Besides those vascular complications, AGE are involved in altered metabolism in many tissues, including adipose tissue (AT) where they contribute to reduced glucose uptake and attenuation of insulin sensitivity. AGE are known to contribute to type 1 diabetes (T1D) through promotion of interleukin (IL)-17 secreting T helper (Th17) cells. AIM: To investigate whether lean adipose-derived stem cells (ASC) could be able to induce IL-17A secretion, with the help of AGE. METHODS: As we have recently demonstrated that ASC are involved in Th17 cell promotion when they are harvested from obese AT, we used the same co-culture model to measure the impact of glycated human serum albumin (G-HSA) on human lean ASC interacting with blood mononuclear cells. IL-17A and pro-inflammatory cytokine secretion were measured by ELISA. Receptor of AGE (RAGE) together with intercellular adhesion molecule 1 (ICAM-1), human leukocyte Antigen (HLA)-DR, cluster of differentiation (CD) 41, and CD62P surface expressions were measured by cytofluorometry. Anti-RAGE specific monoclonal antibody was added to co-cultures in order to evaluate the role of RAGE in IL-17A production. RESULTS: Results showed that whereas 1% G-HSA only weakly potentiated the production of IL-17A by T cells interacting with ASC harvested from obese subjects, it markedly increased IL-17A, but also interferon gamma and tumor necrosis factor alpha production in the presence of ASC harvested from lean individuals. This was associated with increased expression of RAGE and HLA-DR molecule by co-cultured cells. Moreover, RAGE blockade experiments demonstrated RAGE specific involvement in lean ASC-mediated Th-17 cell activation. Finally, platelet aggregation and ICAM-1, which are known to be induced by AGE, were not involved in these processes. CONCLUSION: Thus, our results demonstrated that G-HSA potentiated lean ASC-mediated IL-17A production in AT, suggesting a new mechanism by which AGE could contribute to T1D pathophysiology.

IL-17A contributes to propagation of inflammation but does not impair adipogenesis and/or insulin response, in adipose tissue of obese individuals.

BACKGROUND: Adipose tissue is infiltrated with various immune cells, including Th17 lymphocytes and monocytes/macrophages, in obese individuals. We have previously demonstrated the role of obese adipose-derived stem cells (ob-ASC) and adipocytes (AD) in the mediation of inflammation through promotion of Th17 cells and activation of monocytes. Such an inflammation resulted in impaired ob-ASC adipogenesis and AD insulin response. In the present study, we investigated the role of IL-17A in the impairment of these functions. METHODS: With this aim, we used Secukinumab, a potent human anti-IL17A monoclonal antibody which has been approved for the treatment of some IL-17A related inflammatory diseases, notably Psoriasis. This antibody was added or not to phytohemagglutinin A-activated co-cultures of ob-ASC and mononuclear cells. The conditioning media of those co-cultures were harvested and added to AD ongoing differentiation from ob-ASC. Adipogenesis, insulin sensitivity and secretion of inflammatory cytokines were then measured using qRT-PCR, Western blots and ELISAs, respectively. RESULTS: Surprisingly, we did not observe any direct effect of IL-17A on ob-ASC adipogenesis, despite sensitivity of ob-ASC to IL-17A. Moreover, IL-17A blockade, with the help of Secukinumab, did not lead to the recovery of adipogenesis and insulin response, when these functions were impaired by the presence of an inflammatory conditioning medium. However, the up-regulation of IL6 and IL1B mRNA expression by AD submitted to inflammatory conditioning medium was inhibited in the presence of Secukinumab, which indicates that IL-17A may play a role in the propagation of inflammation towards AD. IN CONCLUSION: we show herein that IL-17A does not play a major role in the impairment of adipogenesis and/or insulin resistance mediated by an inflammatory environment, but contributes to the propagation of inflammation in human obese adipose tissues. This suggests a beneficial effect of anti-IL17A mAb in inflammatory pathologies, where obesity contributes to poorer response to biologic treatments.

Omega-3 Polyunsaturated Fatty Acids Inhibit IL-17A Secretion through Decreased ICAM-1 Expression in T Cells Co-Cultured with Adipose-Derived Stem Cells Harvested from Adipose Tissues of Obese Subjects.

SCOPE: Obese adipose tissue (AT) is infiltrated by inflammatory immune cells including IL-17A-producing-T (Th17) cells. It has been previously demonstrated that adipose-derived stem cells from obese (ob-ASCs), but not lean AT promote Th17 cells. Because n-3 PUFAs are known to inhibit obese AT inflammation, it is tested here whether they could inhibit ob-ASC-mediated IL-17A secretion. METHODS AND RESULTS: The n-3 PUFA precursor, alpha-linolenic acid (ALA), or its derivatives, eicosapentaenoic, or docosahexaenoic acid, is added to co-cultures of human ob-ASCs and mononuclear cells (MNCs). All three inhibited IL-17A, but not IL-1ß, IL-6, nor TNFα  secretion. As a control, palmitic acid (PA), a saturated fatty acid, did not inhibit IL-17A secretion. ALA also inhibited IL-17A secretion mediated by adipocytes differentiated from ob-ASCs. Toll-like-receptor 4 is shown to be involved in ob-ASC-mediated-IL-17A secretion, and to be inhibited by ALA, together with Cyclo-Oxygenase-2 and Signal-Transducer-and-Activator-of-transcription-3. In addition, ALA down-regulated Intercellular-Adhesion-Molecule-1 (ICAM-1) expression in both monocytes and ASCs, which resulted in decreased interactions between ob-ASCs and MNCs, and inhibition of IL-17A secretion. CONCLUSION: It is demonstrated herein that ALA inhibits Th17 cell promotion, through decreased ICAM-1expression in both ob-ASCs and monocytes. This novel mechanism may contribute to explain the beneficial effects of n-3 PUFA in IL-17A-related inflammatory pathologies.