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.

Context and Objectives In obese mice and patients, mineralocorticoid receptor (MR) activation has deleterious consequences on metabolic and cardiovascular parameters. In mice, adipose tissue MR triggers mitochondrial and vascular dysfunction. Adipocyte MR activation induces metabolic and vascular dysfunction in a context of obesity, however, obese adipose tissue is also infiltrated with macrophages, which are capable of expressing MR. Thus, we hypothesised that macrophage MR could also be responsible for metabolic and cardiovascular complications in high‐fat high‐salt diet‐fed mice. Methods We fed myeloid cell‐specific MR knock‐out male and female mice (My‐MRKO) with a 6‐week high fat – high salt diet (60% kcal from fat, 1.2% salt in drinking water) and studied weight gain, whole body and specific organs composition by nuclear magnetic resonance and insulin sensitivity to explore the metabolic phenotype. Blood pressure measurements by plethysmography and vascular reactivity studies by wire myography were also performed to characterise the cardiovascular phenotype. Results My‐MRKO male mice under high fat – high salt diet displayed reduced weight (37.8 g [interquartile range 34.1–40.8] vs 42.5 g [39.5–45.2]; P = 0.0128), preserved muscle mass (61.5 % [55.8–63.3] vs 56.8 % [54.1–58.5]; P = 0.0337) and a strong tendency to decreased fat mass (26.1 % [23.7–33.9] vs 31.7 % [27.1–35.4]; P = 0.0728). Moreover, liver fat content at sacrifice was decreased (5.8 % [2.1–9.1] vs 9.3 % [5.9–13.4]; P = 0.0491). Those effects were not observed in female mice. Fasting glycaemia was decreased in male My‐MRKO mice (9.2 mmol/L [6.4–12.8] vs 13.2 mmol/L [10.4–16.1]; P = 0.0005) and insulin resistance was decreased in both gender (area under curve 9915 [9398–10043] vs 11550 [9795–12848]; P = 0.0458 in males, 8291 [7812–8884] vs 9544 [8918–9735]; P = 0.0177 in females), as assessed by an insulin tolerance test. A clear effect was observed on blood pressure only in female mice (blood pressure 96 mmHg [94–97] vs 106 mmHg [104–109]; P = 0.0004), whereas there was no modification in mesenteric arteries vascular reactivity in both gender. Conclusions Thus, our findings show that myeloid cell‐MR regulates systemic metabolic parameters, highlighting a new role in obesity and its associated complications for MR expressed in myeloid cells. Support or Funding Information Sorbonne Université, Inserm, CARMMA‐RHU