Obesity is a multifaceted, chronic, low-grade inflammation disease characterized by excess accumulation of dysfunctional adipose tissue. It is often associated with the development of cardiovascular (CV) disorders, insulin resistance and diabetes. Under pathological conditions like in obesity, adipose tissue secretes bioactive molecules called ‘adipokines’, including cytokines, hormones and reactive oxygen species (ROS). There is evidence suggesting that oxidative stress, in particular, the ROS imbalance in adipose tissue, may be the mechanistic link between obesity and its associated CV and metabolic complications. Mitochondria in adipose tissue are an important source of ROS and their dysfunction contributes to the pathogenesis of obesity-related type 2 diabetes. Mitochondrial function is regulated by several factors in order to preserve mitochondria integrity and dynamics. Moreover, the renin–angiotensin–aldosterone system is over-activated in obesity. In this review, we focus on the pathophysiological role of the mineralocorticoid receptor in the adipose tissue and its contribution to obesity-associated metabolic and CV complications. More specifically, we discuss whether dysregulation of the mineralocorticoid system within the adipose tissue may be the upstream mechanism and one of the early events in the development of obesity, via induction of oxidative stress and mitochondrial dysfunction, thus impacting on systemic metabolism and the CV system.

Adipose tissue (AT) senescence and mitochondrial dysfunction are associated with obesity. Studies in obese patients and animals demonstrate that the MR (mineralocorticoid receptor) contributes to obesity-associated cardiovascular complications through its specific role in AT. However, underlying mechanisms remain unclear. This study aims to elucidate whether MR regulates mitochondrial function in obesity, resulting in AT premature aging and vascular dysfunction. Obese (db/db) and lean (db/+) mice were treated with an MR antagonist or a specific mitochondria-targeted antioxidant. Mitochondrial and vascular functions were determined by respirometry and myography, respectively. Molecular mechanisms were probed by Western immunoblotting and real-time polymerase chain reaction in visceral AT and arteries and focused on senescence markers and redox-sensitive pathways. db/db mice displayed AT senescence with activation of the p53-p21 pathway and decreased SIRT (sirtuin) levels, as well as mitochondrial dysfunction. Furthermore, the beneficial anticontractile effects of perivascular AT were lost in db/db via ROCK (Rho kinase) activation. MR blockade prevented these effects. Thus, MR activation in obesity induces mitochondrial dysfunction and AT senescence and dysfunction, which consequently increases vascular contractility. In conclusion, our study identifies novel mechanistic insights involving MR, adipose mitochondria, and vascular function that may be of importance to develop new therapeutic strategies to limit obesity-associated cardiovascular complications.

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.

Background: Kidney transplant recipients are prescribed an immunosuppressive therapy (IST) and some of them follow a high fat diet (HFD) despite medical recommendations. Both are frequently associated with gut microbiota changes and metabolic disorders. We aimed at precisely identifying the effect of the IST and the HFD on metabolic parameters and the gut microbiota in mice, and at establishing correlations between the latters. Methods: 8-week-old male mice were treated with IST (a combination of prednisone, mycophenolate mofetil and tacrolimus) or not and were fed HFD or standard chow. Metabolic parameters were measured, and the gut microbiota was explored by the quantification of specific bacterial groups by qPCR and by 16S rDNA sequencing. Results: The HFD increased insulinemia and decreased the fecal proportion of Bacteroidetes and of Bacteroides. The IST increased systolic blood pressure and the fecal proportion of Escherichia coli. The HFD and the IST administered together resulted in an additive effect on glucose intolerance, high fasting blood glucose, homeostasis model assessment of insulin resistance (HOMA-IR), percentage of fat mass, blood triglyceride, blood cholesterol, and endotoxemia. On the opposite, the HFD and the IST had antagonistic effects on body weight, the proportion of Firmicutes, the Firmicutes/Bacteroidetes ratio, and the proportion of Clostridium leptum, Bifidobacterium, and Lactobacillus in the feces. Finally, we found that the correlations between gut bacterial communities and metabolic consequences of the HFD were altered by the IST. Conclusion: The IST and the HFD have specific consequences on the gut microbiota and metabolism. We hypothesize that the metabolic consequences are at least partially mediated by IST/HFD-induced dysbiosis.

Animals develop through discrete life stages with specific goals, such as growth or reproduction. Achieving these goals may require temporary changes in the function of certain organs, but these adaptations remain poorly understood. In Drosophila , the juvenile phase is characterized by a several-hundred-fold increase in body mass, which culminates in a rapid growth spurt before puberty. Here, we show that this growth spurt is supported by acute remodeling of gut metabolism. Midway through the juvenile phase, steroid hormone and hepatocyte nuclear factor 4 induce digestive function, lipid metabolism and nutrient export in the intestine, thereby accelerating growth and maturation. Gut metabolic remodeling ceases at puberty but has a lasting impact on physiology, enhancing adult reproductive fitness and resilience to environmental stress. Our work identifies an endocrine-metabolic axis that synchronizes gut function with developmental demands, and provides insights into how systemic signals dynamically remodel organ metabolism to optimize life history strategies.

L’obésité est une maladie pandémique caractérisée par un excès de tissu adipeux (TA), à l’origine de complications métaboliques et cardiovasculaires dont l’origine physiopathologique reste mal identifiée. Ce travail de thèse étudie le rôle du récepteur minéralocorticoïde (MR) dans la physiopathologie de l’obésité et de ses complications. Ce récepteur nucléaire, facteur de transcription, régule l’homéostasie hydrosodée rénale et colique. Il est également exprimé dans d’autres organes et cellules (vaisseaux sanguins, adipocytes, macrophages) et son expression est augmentée dans le TA des patients obèses. Notre hypothèse est que l’activation excessive du MR dans le TA induit un dysfonctionnement organique causé par un stress oxydant augmenté, des anomalies de la fonction mitochondriale et un vieillissement prématuré. À l’aide de modèles murins transgéniques spontanément obèses ou à l’obésité provoquée par un régime riche en lipides, et présentant une modification de l’expression du MR dans les adipocytes ou dans la lignée myéloïde, nous avons démontré que l’activation du MR dans le TA blanc viscéral induit une augmentation du stress oxydant liée à une altération de la respiration et du contrôle qualité mitochondriaux, ainsi qu’une sénescence prématurée. Nos données démontrent pour la première fois un lien entre activation du MR, dysfonction mitochondriale et vieillissement dans le TA blanc, permettant de mieux comprendre le rôle du MR dans l’obésité et de proposer de nouvelles pistes de recherche et stratégies thérapeutiques pour lutter contre les comorbidités qui y sont associées.