Adipose Tissue Dysfunction In Obesity Research Articles

Obesity and Autoimmunity Epidemic: The Role of Immunometabolism.

The relationship between obesity and autoimmune diseases has attracted significant attention in recent years, highlighting the multifaceted connection between metabolic dysregulation and loss of self-immune tolerance. Compelling epidemiological evidence has revealed an elevated prevalence of autoimmune diseases among overweight or obese individuals, suggesting a potential causal link. Mechanistically, adipose tissue is a key immunometabolic organ that secretes an array of adipocytokines that can facilitate proinflammatory immune responses against self-antigens. Indeed, adipose tissue dysfunction in obesity fosters a state of chronic low-grade inflammation, which may contribute to the so-called accelerator hypothesis, in which circulating self-autoreactive T cells can easily lose their regulatory mechanisms, resulting in self-tissue damage and autoinflammation. In this review, we elucidate the intricate immunometabolic pathomechanisms underlying the obesity and autoimmunity epidemic, and we explore innovative therapeutic avenues that could be pivotal for advancing public health initiatives in the context of this epidemic.

Endothelin-1 down-regulates nuclear factor erythroid 2-related factor-2 and contributes to perivascular adipose tissue dysfunction in obesity.

Perivascular adipose tissue (PVAT) negatively regulates vascular muscle contraction. However, in the context of obesity, the PVAT releases vasoconstrictor substances that detrimentally affect vascular function. A pivotal player in this scenario is the peptide endothelin-1 (ET-1), which induces oxidative stress and disrupts vascular function. The present study postulates that obesity augments ET-1 production in the PVAT, decreases the function of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, further increasing reactive oxygen species (ROS) generation, culminating in PVAT dysfunction. Male C57BL/6 mice were fed either a standard or a high-fat diet for 16 weeks. Mice were also treated with saline or a daily dose of 100 mg·kg-1 of the ETA and ETB receptor antagonist Bosentan, for 7 days. Vascular function was evaluated in thoracic aortic rings, with and without PVAT. Mechanistic studies utilized PVAT from all groups and cultured WT-1 mouse brown adipocytes. PVAT from obese mice exhibited increased ET-1 production, increased ECE1 and ETA gene expression, loss of the anticontractile effect, as well as increased ROS production, decreased Nrf2 activity, and downregulated expression of Nrf2-targeted antioxidant genes. PVAT of obese mice also exhibited increased expression of Tyr216-phosphorylated-GSK3β and KEAP1, but not BACH1 - negative Nrf2 regulators. Bosentan treatment reversed all these effects. Similarly, ET-1 increased ROS generation and decreased Nrf2 activity in brown adipocytes, events mitigated by BQ123 (ETA receptor antagonist). These findings place ET-1 as a major contributor to PVAT dysfunction in obesity and highlight that pharmacological control of ET-1 effects restores PVAT's cardiovascular protective role.

2054-LB: Mitigating Adipose Tissue Dysfunction and Insulin Resistance in Obesity via SVEP1 Peptide-Mediated Suppression of Adipose Tissue Macrophage-Induced Inflammation

Introduction: Adipose tissue dysfunction in obesity poses a critical threat, causing metabolic impairment and systemic inflammation. This study explores the therapeutic potential of a peptide from SVEP1, targeting its integrin α9β1 receptor, to alleviate obesity-induced adipose dysfunction and insulin resistance by reducing pro-inflammatory macrophage activity. Methods: We comprehensively examined the peptide's effect on adipose tissue dysfunction using in silico predictive binding, LPS-activated mono and co-culture cell systems, and diet-induced obese mice. Results: Analysis of integrin α9β1 revealed specific expression in myeloid cells, particularly dysfunctional adipose tissue macrophages. In silico predictions confirmed the peptide's integrin affinity and ability to block ligand interactions. Peptide-treated LPS-activated BMDM exhibited reduced adhesion and mobility on decellularized matrices from adipocytes. The peptide suppressed pro-inflammatory activation, by inhibiting the MAPK and NF-κB pathways, altered transcriptomics, and reduced cytokine production in ex vivo isolated adipose tissue macrophages. Epididymal adipose tissue peptide administration in diet-induced obese mice reduced body and tissue weight, improved glucose sensitivity, hepatic function, and lessened adipose inflammation through modulated macrophage phenotype. Bulk and single-cell transcriptomics indicated decreased pro-inflammatory responses, improving adipocyte status, insulin sensitivity, and thermogenic capacity due to the anti-inflammatory state of tissue macrophages and upregulated mitochondrial activity. Conclusions: The SVEP1-derived peptide emerges as a regulator of macrophages in obesity, effectively mitigating inflammation and restoring glucose homeostasis. This study offers insights into potential therapeutic avenues for addressing adipose tissue dysfunction. Disclosure N. Kislev: None. N. Kavin: None. R. Izgilov: None. D. Benayahu: None.

Hippo-YAP/TAZ-ROS signaling axis regulates metaflammation induced by SelenoM deficiency in high-fat diet-derived obesity

Hippo-YAP/TAZ-ROS signaling axis regulates metaflammation induced by SelenoM deficiency in high-fat diet-derived obesity

Obesity as a main component of metabolic syndrome and a risk factor for comorbidity

Obesity is an important medical and social problem, it occupies one of the leading places among cardiovascular risk factors. Obesity is a major component of the metabolic syndrome. It has a close pathogenetic relationship with its other manifestations, as a result of which a portrait of a comorbid patient is formed. The article presents data on the prevalence, criteria for diagnosing obesity, the relationship of obesity with other components of the metabolic syndrome is shown. The role of adipose tissue dysfunction in obesity on the development and progression of insulin resistance, atherosclerosis, as well as its relationship with non-alcoholic fatty liver disease and arterial hypertension is discussed. It is shown that obesity is a comorbidity factor and the basis of the metabolic syndrome, the leading pathogenetic mechanism in the formation and progression of its components, preceding their occurrence. This allows us to conclude that weight loss can reduce cardiovascular risks, reduce the manifestations of the metabolic syndrome, and in some cases even eliminate them completely.

Inflammatory response to bacterial lipopolysaccharide drives iron accumulation in human adipocytes

The association among increased inflammation, disrupted iron homeostasis, and adipose tissue dysfunction in obesity has been widely recognized. However, the specific impact of inflammation on iron homeostasis during human adipogenesis and in adipocytes remains poorly understood. In this study, we investigated the effects of bacterial lipopolysaccharide (LPS) on iron homeostasis during human adipocyte differentiation, in fully differentiated adipocytes, and in human adipose tissue. We found that LPS-induced inflammation hindered adipogenesis and led to a gene expression profile indicative of intracellular iron accumulation. This was accompanied by increased expression of iron importers (TFRC and SLC11A2), markers of intracellular iron accumulation (FTH, CYBA, FTL, and LCN2), and decreased expression of iron exporter-related genes (SLC40A1), concomitant with elevated intracellular iron levels. Mechanistically, RNA-seq analysis and gene knockdown experiments revealed the significant involvement of iron importers SLC39A14, SLC39A8, and STEAP4 in LPS-induced intracellular iron accumulation in human adipocytes. Notably, markers of LPS signaling pathway-related inflammation were also associated with a gene expression pattern indicative of intracellular iron accumulation in human adipose tissue, corroborating the link between LPS-induced inflammation and iron accumulation at the tissue level. In conclusion, our findings demonstrate that induction of adipocyte inflammation disrupts iron homeostasis, resulting in adipocyte iron overload.

Irisin: A Possible Marker of Adipose Tissue Dysfunction in Obesity.

Adipose tissue (AT) secretes pro- and anti-inflammatory cytokines involved in AT homeostasis, including tumor necrosis factor-α (TNFα) and irisin. The functionality of AT is based on a regulated equilibrium between adipogenesis and extracellular matrix (ECM) remodeling. We investigated the contributions of adipose progenitors (ASCs) and adipocytes (AMCs) to TNFα-induced ECM remodeling and a possible implication of irisin in AT impairment in obesity. ASCs and AMCs were exposed to TNFα treatment and nuclear factor-kappa (NF-kB) pathway was investigated: Tissue Inhibitor of Metalloproteinase (TIMP-1), Twist Family Transcription Factor 1 (TWIST-1), and peroxisome proliferator-activated receptor-γ (PPARγ) expression levels were analyzed. The proteolytic activity of matrix metalloproteinases (MMPs) -2 and -9 was analyzed by zymography, and the irisin protein content was measured by ELISA. In inflamed AMCs, a TIMP-1/TWIST-1 imbalance leads to a drop in PPARγ. Adipogenesis and lipid storage ability impairment come with local tissue remodeling due to MMP-9 overactivation. In vitro and ex vivo measurements confirm positive correlations among inflammation, adipose secreting irisin levels, and circulating irisin levels in patients with visceral obesity. Our findings identify the NF-kB downstream effectors as molecular initiators of AT dysfunction and suggest irisin as a possible AT damage and obesity predictive factor.

CCL17 and CCL22 chemokines are upregulated in human obesity and play a role in vascular dysfunction.

Chemokines are known to play critical roles mediating inflammation in many pathophysiological processes. The aim of this study was to investigate the role of chemokine receptor CCR4 and its ligands CCL17 and CCL22 in human morbid obesity. Circulating levels of CCL17 and CCL22 were measured in 60 morbidly obese patients (mean age, 45 ± 1 years; body mass index/BMI, 44 ± 1 kg/m2) who had undergone bariatric bypass surgery, and 20 control subjects. Paired subcutaneous (SCAT) and visceral adipose tissue (VCAT) from patients were analysed to measure expression of CCR4 and its ligands by RT-PCR, western blot and immunohistochemical analysis. The effects of CCR4 neutralization ex vivo on leukocyte-endothelial cells were also evaluated. Compared with controls, morbidly obese patients presented higher circulating levels of CCL17 (p=0.029) and CCL22 (p<0.001) and this increase was positively correlated with BMI (p=0.013 and p=0.0016), and HOMA-IR Index (p=0.042 and p< 0.001). Upregulation of CCR4, CCL17 and CCL22 expression was detected in VCAT in comparison with SCAT (p<0.05). Using the parallel-plate flow chamber model, blockade of endothelial CCR4 function with the neutralizing antibody anti-CCR4 in morbidly obese patients significantly reduced leucocyte adhesiveness to dysfunctional endothelium, a key event in atherogenesis. Additionally, CCL17 and CCL22 increased activation of the ERK1/2 mitogen-activated protein kinase signalling pathway in human aortic endothelial cells, which was significantly reduced by CCR4 inhibition (p=0.016 and p<0.05). Based on these findings, pharmacological modulation of the CCR4 axis could represent a new therapeutic approach to prevent adipose tissue dysfunction in obesity.

Obesity and Aging. General Aspects

Obesity is associated with an increased risk of acute and chronic diseases, including hypertension, stroke, myocardial infarction, cardiovascular disease, diabetes, cancer, and reduces life expectancy by up to 20 years, increasing the risk of premature death. It has been shown that the metabolic changes associated with obesity are similar to those observed with aging. Thus, obesity and aging have a similar range of phenotypes, such as impaired genome integrity, mitochondrial function, accumulation of intracellular macromolecules, weakened immunity, and systemic inflammation. The commonality of mechanisms may underlie the acceleration of aging processes, both at the molecular and systemic levels. Thus, understanding the mechanisms of adipose tissue dysfunction in obesity can provide insight into the processes that contribute to the metabolic dysfunction associated with the aging process. The current review will examine the molecular and cellular mechanisms that underlie obesity and aging, and how obesity can activate the aging process, initiating the early onset of aging-associated chronic diseases.

Notch activation shifts the fate decision of senescent progenitors toward myofibrogenesis in human adipose tissue.

Senescence is a key event in the impairment of adipose tissue (AT) function with obesity and aging but the underlying molecular and cellular players remain to be fully defined, particularly with respect to the human AT progenitors. We have found distinct profiles of senescent progenitors based on AT location between stroma from visceral versus subcutaneous AT. In addition to flow cytometry, we characterized the location differences with transcriptomic and proteomic approaches, uncovering the genes and developmental pathways that are underlying replicative senescence. We identified key components to include INBHA as well as SFRP4 and GREM1, antagonists for the WNT and BMP pathways, in the senescence-associated secretory phenotype and NOTCH3 in the senescence-associated intrinsic phenotype. Notch activation in AT progenitors inhibits adipogenesis and promotes myofibrogenesis independently of TGFβ. In addition, we demonstrate that NOTCH3 is enriched in the premyofibroblast progenitor subset, which preferentially accumulates in the visceral AT of patients with an early obesity trajectory. Herein, we reveal that NOTCH3 plays a role in the balance of progenitor fate determination preferring myofibrogenesis at the expense of adipogenesis. Progenitor NOTCH3 may constitute a tool to monitor replicative senescence and to limit AT dysfunction in obesity and aging.

The Adipocyte-Macrophage Relationship in Cancer: A Potential Target for Antioxidant Therapy.

Obesity has emerged as a major public health concern with a staggering 39% worldwide prevalence as of 2021. Given the magnitude of the problem and considering its association with chronic low-grade systemic inflammation, it does not come as a surprise that obesity is now considered one of the major risk factors for the development of several chronic diseases, such as diabetes, cardiovascular problems, and cancer. Adipose tissue dysfunction in obesity has taken center stage in understanding how changes in its components, particularly adipocytes and macrophages, participate in such processes. In this review, we will initially focus on how changes in adipose tissue upon excess fat accumulation generate endocrine signals that promote cancer development. Moreover, the tumor microenvironment or stroma, which is also critical in cancer development, contains macrophages and adipocytes, which, in reciprocal paracrine communication with cancer cells, generate relevant signals. We will discuss how paracrine signaling in the tumor microenvironment between cancer cells, macrophages, and adipocytes favors cancer development and progression. Finally, as reactive oxygen species participate in many of these signaling pathways, we will summarize the information available on how antioxidants can limit the effects of endocrine and paracrine signaling due to dysfunctional adipose tissue components in obesity.

Influence of Protein Carbonylation on Human Adipose Tissue Dysfunction in Obesity and Insulin Resistance

Background: Obesity is characterized by adipose tissue dysregulation and predisposes individuals to insulin resistance and type 2 diabetes. At the molecular level, adipocyte dysfunction has been linked to obesity-triggered oxidative stress and protein carbonylation, considering protein carbonylation as a link between oxidative stress and metabolic dysfunction. The identification of specific carbonylated proteins in adipose tissue could provide novel biomarkers of oxidative damage related to metabolic status (i.e prediabetes). Thus, we aimed at characterizing the subcutaneous and omental human adipose tissue carbonylome in obesity-associated insulin resistance. Methods: 2D-PAGE was used to identify carbonylated proteins, and clinical correlations studies and molecular biology approaches including intracellular trafficking, reactive oxygen species assay, and iron content were performed using in vitro models of insulin resistance. Results: The carbonylome of human adipose tissue included common (serotransferrin, vimentin, actin, and annexin A2) and depot-specific (carbonic anhydrase and α-crystallin B in the subcutaneous depot; and α-1-antitrypsin and tubulin in the omental depot) differences that point out the complexity of oxidative stress at the metabolic level, highlighting changes in carbonylated transferrin expression. Posterior studies using in vitro prediabetic model evidence alteration in transferrin receptor translocation, linked to the prediabetic environment. Finally, ligand-receptor molecular docking studies showed a reduced affinity for carbonylated transferrin binding to its receptor compared to wild-type transferrin, emphasizing the role of transferrin carbonylation in the link between oxidative stress and metabolic dysfunction. Conclusions: The adipose tissue carbonylome contributes to understanding the molecular mechanism driving adipocyte dysfunction and identifies possible adipose tissue carbonylated targets in obesity-associated insulin resistance.

Mirabegron relaxes arteries from human visceral adipose tissue through antagonism of α1-adrenergic receptors

Mirabegron relaxes arteries from human visceral adipose tissue through antagonism of α1-adrenergic receptors

RELATIONSHIP BETWEEN SELENIUM NUTRITIONAL STATUS AND MARKERS OF LOW-GRADE CHRONIC INFLAMMATION IN OBESE WOMEN.

Low-grade chronic inflammation is one of the main disorders that characterize adipose tissue dysfunction in obesity and is an important element in the pathogenesis of several comorbidities. In this context, selenium is an essential micronutrient that exerts important anti-inflammatory functions, and the role of selenium in controlling inflammation associated with obesity is not well defined. Thus, this study aimed to evaluate the relationship between markers of the nutritional status of selenium and low-grade chronic inflammation in obese women. This cross-sectional study included 81 women aged between 18 and 50years, who were divided into two groups according to body mass index (BMI): the obesity group (n = 38) and normal weight group (n = 43). Selenium intake was assessed by 3-day diet records. The plasma, erythrocyte, and urinary selenium concentrations were determined using inductively coupled plasma optical emission spectrometry. The analysis of serum cytokines interleukin (IL)-8, IL-1β, IL-6, IL-10, and tumor necrosis factor alpha (TNFα) was performed using flow cytometry. The results of this study revealed that the obese women had higher dietary intake of selenium than eutrophic women. However, obese participants showed decreased selenium concentrations in plasma and erythrocytes, in parallel with increased concentrations of selenium in the urine. Regarding the inflammatory parameters, obese women exhibited higher concentrations of IL-6 and lower concentrations of the cytokines IL-8, IL-1β, and TNFα than eutrophic women. In the binary logistic regression analysis, erythrocyte selenium was considered an independent predictor of the serum concentrations of cytokine IL-8 in obese women, reflecting the anti-inflammatory action of this micronutrient.

Understanding the adipose tissue acetylome in obesity and insulin resistance

Understanding the adipose tissue acetylome in obesity and insulin resistance

Abstract 14057: IL-19 Preserves the Metabolic Activity of Adipocytes in Obesity

Lack of compensatory vascularization causes hypoxia with adipose tissue dysfunction in obesity. Dysfunctional adipocytes instigate systemic low-grade inflammation which is associated with increased morbidity and mortality of metabolic disorders and related cardiovascular disease. A remaining challenge in the field is how to preserve adipocyte metabolic function by suppressing the negative aspect of inflammation, without blocking its angiogenic function. We investigated the role of IL-19, a uniquely immuno-modulatory, pro-angiogenic interleukin expressed also in adipose tissue. We hypothesize that IL-19 acts as a novel adipokine whose expression in expanding adipose depots is essential for maintaining glucose homeostasis. We report that IL-19 is expressed in adipose tissue at both the transcript and protein level and its expression is increased in inflamed visceral adipose tissue but not subcutaneous adipose tissue (p&lt;0.05). Utilizing Il19 -/- knockout mice, we found the loss of IL-19 leads to a metabolic phenotype characterized by reduced glucose and insulin tolerance, increased adipose tissue hypoxia and fibrosis, decreased adipose tissue vessel density and increased adipocyte hypertrophy both in response to standard chow diet and chronic high fat diet (p&lt;0.05). Acute treatment with IL-19 reduced glucose and insulin intolerance in obese wild-type mice (p&lt;0.05). In primary murine epididymal adipocytes the addition of IL-19 leads to increased glucose uptake (p&lt;0.05). These metabolic actions of IL-19 were linked to upregulation of the insulin type-2 receptor and subsequent increased expression/phosphorylation of the protein kinase B (Akt) in adipocytes. Overall, these data propose that IL-19 has novel therapeutic potential in that it can effectively allow adipose tissue expansion without concomitant inflammation and insulin insensitivity.

An immediate post op and follow up assessment of circulating adipo-cytokines after bariatric surgery in morbid obesity

An immediate post op and follow up assessment of circulating adipo-cytokines after bariatric surgery in morbid obesity

Lrg1 is a Driver of Brown Adipose Tissue Dysfunction in Obesity

Background Energy is stored as lipid within white adipose tissue (WAT) however, over-nutrition can lead to excess WAT, obesity and metabolic disease. Brown adipose tissue (BAT) has a primary role in energy expenditure through futile cycling of the electron transport chain (ETC) to generate heat. BATs heat producing capacity may be a novel approach to treating obesity. Adult humans possess metabolically active BAT, but the onset of obesity can reduce BAT thermogenic activity and mass. Obesity can bring about morphological changes to BAT, causing BAT to resemble WAT in a process termed “whitening”. WAT is a well-known endocrine organ. Specific endocrine signals from WAT could be responsible for reduced BAT activity in obesity. Leucine-rich-α2-glycoprotein 1 (LRG1) is an adipose-associated secretory protein and potential adipokine, with plasma levels positively correlated to body mass index in humans. Hypothesis It is hypothesized that LRG1 is an adipokine which negatively regulates thermogenesis in BAT and contributes to obesity related loss of BAT. Methods Male Lrg1 global knockout (KO) mice or wild type (WT) controls were fed standard chow (STD) or high fat diet (HFD) for 10 weeks. At 18 weeks of age systemic and BAT metabolic characteristics were determined by whole body indirect calorimetry, high-resolution tissue respirometry, quantitative PCR and immunoblots. Results After 10 weeks of HFD feeding Lrg1 KO mice fed STD and HFD had significantly higher percentage of body mass comprised of BAT than WT controls (Figure 1A). Lrg1 KO mice fed HFD had a lower respiratory exchange ratio (RER), indicating a greater use of fat oxidation compared to WT controls (Figure 1B). Mitochondrial respiration was used to measure changes in cellular energy. In response to HFD WT mice exhibit a decrease in mitochondrial respiration through complex 1 of the electron transport chain (ETC) (Figure 2A). The mitochondrial function of Lrg1 KO mice BAT is protected from HFD-induced dysfunction at Complex 1 of the ETC (Figure 2A). Uncoupling protein 1 (UCP1), a key protein involved in thermogenesis, Ucp1 mRNA is significantly increased in the BAT of Lrg1 KO STD and HFD fed mice compared to WT (Figure 2B). Ucp1 mRNA expression increase in Lrg1 KO mice was confirmed by measuring UCP1 protein with an immunoblot (Figure 2C). Conclusion Loss of Lrg1 protects BAT from dysfunction in diet-induced obesity.

Adipocyte‐derived Exosomes: Novel Insight in the Link between Obesity and Breast Cancer

Introduction Obesity has an intricate connection to both risk and clinical behaviour of breast cancer. Adipose tissue dysfunction in obesity results in a release of many adipokines that it is well known to promote breast tumor biology. In addition to soluble factors, exosomes (exo), small membrane-derived vesicles secreted by both normal and malignant cells, have been recently suggested to act as additional mediators of cell-to-cell communication. However, a clear understanding in the role of adipocyte-derived exo in mediating the adverse effects of obesity on BC is still lacking. Herein, we evaluated the involvement of adipocyte-derived exo in sustaining BC development and progression. Methods Exo were isolated and fully characterized from conditioned media (CM) of differentiated 3T3-L1 adipocytes (3T3-L1 A), a well-recognized ‘in vitro’ model of white adipocytes. We tested the effects of 3T3-L1 A exo in modulating the proliferation (MTT/soft agar assays), motility/invasion (wound healing/Boyden Chamber migration/invasion assays), and stemness (mammosphere forming efficiency/Limiting Dilution assays) of estrogen receptor α (ERα)-positive MCF-7 and triple-negative MDA-MB-231 BC cells. We also assessed co-culture experiments between BC cells and CM derived from adipocytes isolated from human mammary adipose tissues (MAT) of adult normal weight and obese women. Results The treatment with 3T3-L1 A exo significantly increased the number of colonies of MCF-7 and MDA-MB-231 cells in anchorage-independent soft agar growth assay. Also, we found that 3T3-L1 A exo induced a more aggressive phenotype in both BC cells in terms of migration, invasion and stemness. In accordance with these data, we found that 3T3-L1 A exo significantly induced the expression of the mRNA levels of genes encoding several proteins involved in Epithelial to Mesenchymal Transition (EMT) and associated with stem cell phenotype. To gain insight into the molecular mechanism we focused our attention on the expression and activity of HIF-1α, a well-known regulator of hypoxic response, involved in invasion, migration, EMT and metastasis in BC. Interestingly, 3T3-L1 A exo increased the expression of HIF-1α and its target genes, and the use of a HIF-1α translation inhibitor reduced migration and invasion capabilities induced by exo. Finally, we found that CM derived from MAT increased the migratory abilities of both employed cells in a significantly higher extent with MAT obese-CM and these effects were completely reversed in the presence of a specific exo uptake inhibitor. Conclusions Our data suggest that adipocyte exo contribute to a more aggressive BC phenotype. This may open new avenues for identifying novel specific biomarkers and innovative therapeutic strategies (i.e. HIF-1α inhibitors) in BC treatment, especially in obese patients.

Adipocyte-Mineralocorticoid Receptor Alters Mitochondrial Quality Control Leading to Mitochondrial Dysfunction and Senescence of Visceral Adipose Tissue.

Mineralocorticoid receptor (MR) expression is increased in the adipose tissue (AT) of obese patients and animals. We previously demonstrated that adipocyte-MR overexpression in mice (Adipo-MROE mice) is associated with metabolic alterations. Moreover, we showed that MR regulates mitochondrial dysfunction and cellular senescence in the visceral AT of obese db/db mice. Our hypothesis is that adipocyte-MR overactivation triggers mitochondrial dysfunction and cellular senescence, through increased mitochondrial oxidative stress (OS). Using the Adipo-MROE mice with conditional adipocyte-MR expression, we evaluated the specific effects of adipocyte-MR on global and mitochondrial OS, as well as on OS-induced damage. Mitochondrial function was assessed by high throughput respirometry. Molecular mechanisms were probed in AT focusing on mitochondrial quality control and senescence markers. Adipo-MROE mice exhibited increased mitochondrial OS and altered mitochondrial respiration, associated with reduced biogenesis and increased fission. This was associated with OS-induced DNA-damage and AT premature senescence. In conclusion, targeted adipocyte-MR overexpression leads to an imbalance in mitochondrial dynamics and regeneration, to mitochondrial dysfunction and to ageing in visceral AT. These data bring new insights into the MR-dependent AT dysfunction in obesity.