Mineralocorticoid Receptor in Novel Target Tissues: A Closer Look at the Adipocyte

In addition to the well-documented role in the kidney, the mineralocorticoid receptor (MR) has been recently identified in different “non-classical” target tissues, such as the brain, the heart, vasculature, macrophages/monocytes, and adipose tissue. In this context, the MR is involved in adipocyte fundamental processes such as differentiation, autophagy, and adipokine secretion. Excessive activation of the MR contributes to metabolic derangements occurring in mice with obesity and metabolic syndrome. Interestingly, MR pharmacological blockade in murine models of obesity has led to protection from weight gain and adipocyte dysfunctions. Unfortunately, there is still a lack of knowledge on the metabolic effects of MR antagonists, and larger clinical studies are deemed necessary to clarify the metabolic role of MR blockade in humans. This review discusses the role of MR in adipose tissue, focusing on regulation by MR of key cellular processes occurring in the adipocyte. The molecular pathways affected by MR activation or blockade in adipose tissue have been investigated only in part. Hence, more studies are necessary to get more insights in the role of aldosterone/MR in this “non-classical” target tissue and to better understand its potential implications in obesity and metabolic syndrome

QoS-Aware Fully Decentralized Service Assembly

Abstract—Large, distributed software systems are increasingly common in today geographically distributed IT infrastructures. A key challenge for the software engineering community is how to efficiently and effectively manage such complex systems. Extending software services with autonomic capabilities has been suggested as a possible way to address this challenge. Ideally, selfmanagement capabilities should be based on fully distributed, peer-to-peer (P2P) architectures in order to try to overcome the scalability and robustness problems of centralized solutions. Within this context, we propose an approach for the adaptive self-assembly of distributed services, based on a simple epidemic protocol. Our approach is based on the three-layer reference model for adaptive systems, and is centered on the use of a gossip protocol to achieve decentralized information dissemination and decision making. The goal of our system is to build and maintain an assembly of services that, besides functional requirements, is able to fulfill global quality of service (QoS) and structural requirements. A set of simulation experiments is used to assess the effectiveness of our approach in terms of convergence speed towards the optimal solution, and resilience to failures. I

Cellular mechanisms of MR regulation of adipose tissue physiology and pathophysiology

In addition to the well-documented expression and activity of the mineralocorticoid receptor (MR) in the kidney, in the last decade research on MR has also revealed its important role in regulating functions of extrarenal tissues, including adipose tissue, where MR is involved in adipocyte fundamental processes such as differentiation, autophagy and adipokine secretion. MR expression is increased in adipose tissue of murine models of obesity and in obese human subjects, suggesting that over-activation of the mineralocorticoid signaling leads to dysfunctional adipocyte and associated metabolic disorders. Notably, pharmacological blockade of MR prevents metabolic dysfunctions observed in obese mice and suggests a potential therapeutic use of MR antagonists in the treatment of obesity and metabolic syndrome. However, the molecular pathways affected by MR blockade have been poorly investigated. This review summarizes the functions of MR in the adipocyte, discusses potential signaling pathways mediating MR action, and describes post-translational modifications regulating its activity

Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease

The mineralocorticoid receptor (MR) was first identified as a blood pressure regulator, modulating renal sodium handling in response to its principal ligand aldosterone. The mineralocorticoid receptor is also expressed in many tissues other than the kidney, such as adipose tissue, heart and vasculature. Recent studies have shown that MR plays a relevant role in the control of cardiovascular and metabolic function, as well as in adipogenesis. Dysregulation of aldosterone/MR signaling represents an important cause of disease as high plasma levels of aldosterone are associated with hypertension, obesity and increased cardiovascular risk. Aldosterone displays powerful vascular effects and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Mineralocorticoid receptor activation regulates genes involved in vascular and cardiac fibrosis, calcification and inflammation. This review focuses on the role of novel potential biomarkers related to aldosterone/MR system that could help identify cardiovascular and metabolic detrimental conditions, as a result of altered MR activation. Specifically, we discuss: (1) how MR signaling regulates the number and function of different subpopulations of circulating and intra-tissue immune cells; (2) the role of aldosterone/MR system in mediating cardiometabolic diseases induced by obesity; and (3) the role of several MR downstream molecules as novel potential biomarkers of cardiometabolic diseases, end-organ damage and rehabilitation outcome

Neuroendocrine and metabolic effects of low-calorie and non-calorie sweeteners

Since excessive sugar consumption has been related to the development of chronic metabolic diseases prevalent in the western world, the use of sweeteners has gradually increased worldwide over the last few years. Although low- and non-calorie sweeteners may represent a valuable tool to reduce calorie intake and prevent weight gain, studies investigating the safety and efficacy of these compounds in the short- and long-term period are scarce and controversial. Therefore, future studies will need to elucidate the potential beneficial and/or detrimental effects of different types of sweeteners on metabolic health (energy balance, appetite, body weight, cardiometabolic risk factors) in healthy subjects and patients with diabetes, obesity and metabolic syndrome. In this regard, the impact of different sweeteners on central nervous system, gut hormones and gut microbiota is important, given the strong implications that changes in such systems may have for human health. The aim of this narrative review is to summarize the current evidence for the neuroendocrine and metabolic effects of sweeteners, as well as their impact on gut microbiota. Finally, we briefly discuss the advantages of the use of sweeteners in the context of very-low calorie ketogenic diets

Mineralocorticoid receptor in adipocytes and macrophages: a promising target to fight metabolic syndrome

Aldosterone is the primary ligand for the mineralocorticoid receptor (MR) and has been considered long time a "renal" hormone, acting at this site as a key regulator of plasma volume, electrolyte homeostasis and blood pressure. A new exciting era of MR biology began with the identification of MR in different non-epithelial tissues such as brain, heart, vessels, macrophages/monocytes, and adipose tissue. The distribution of MR in such a wide range of tissues has suggested novel and unexpected roles for MR, for example in energy metabolism and inflammation. An increasing body of evidence suggests a detrimental effect of aldosterone excess on the development of metabolic alterations. Disturbances in glucose metabolism due to inappropriate activation of MR are frequently observed in patients with primary aldosteronism as well as in obese subjects. MR antagonists have beneficial effects on glucose tolerance and metabolic parameters in experimental animals, whereas their role in humans remains unclear. The aim of this review is to discuss the pathophysiology of MR activation in experimental models, particularly at the level of adipocytes and macrophages, to discuss novel and sometimes contrasting insights from emerging studies, and to highlight deficiencies in the field

Inhibition of vascular c-Jun N-terminal kinase 2 improves obesity-induced endothelial dysfunction after Roux-en-Y gastric bypass

BACKGROUND: Roux-en-Y gastric bypass (RYGB) reduces obesity-associated comorbidities and cardiovascular mortality. RYGB improves endothelial dysfunction, reducing c-Jun N-terminal kinase (JNK) vascular phosphorylation. JNK activation links obesity with insulin resistance and endothelial dysfunction. Herein, we examined whether JNK1 or JNK2 mediates obesity-induced endothelial dysfunction and if pharmacological JNK inhibition can mimic RYGB vascular benefits. METHODS AND RESULTS: After 7 weeks of a high-fat high-cholesterol diet, obese rats underwent RYGB or sham surgery; sham-operated ad libitum-fed rats received, for 8 days, either the control peptide D-TAT or the JNK peptide inhibitor D-JNKi-1 (20 mg/kg per day subcutaneous). JNK peptide inhibitor D-JNKi-1 treatment improved endothelial vasorelaxation in response to insulin and glucagon-like peptide-1, as observed after RYGB. Obesity increased aortic phosphorylation of JNK2, but not of JNK1. RYGB and JNK peptide inhibitor D-JNKi-1 treatment blunted aortic JNK2 phosphorylation via activation of glucagon-like peptide-1-mediated signaling. The inhibitory phosphorylation of insulin receptor substrate-1 was reduced, whereas the protein kinase B/endothelial NO synthase pathway was increased and oxidative stress was decreased, resulting in improved vascular NO bioavailability. CONCLUSIONS: Decreased aortic JNK2 phosphorylation after RYGB rapidly improves obesity-induced endothelial dysfunction. Pharmacological JNK inhibition mimics the endothelial protective effects of RYGB. These findings highlight the therapeutic potential of novel strategies targeting vascular JNK2 against the severe cardiovascular disease associated with obesity

Evaluation of autophagy in lymphocyte populations during atherosclerotic plaque progression with flow cytometry

Atherosclerosis is a chronic inflammatory disorder of the large arteries and represents the primary cause of heart disease and stroke. The exact cause of atherosclerosis is not known. A variety of studies show that autophagy deficiency may be pro-atherogenic and the role of autophagy in smooth muscle cells, macrophages and endothelial cells has been investigated. However, to date no studies addressed the effect of autophagy on lymphocyte subsets playing a role in plaque formation and development. The present project aims to better clarify the role played by autophagy in lymphocytes homeostasis in human atherosclerotic plaques. We characterized lymphocyte populations in different types of lesion by using flow cytometry. In particular, we detected OX40 as marker for conventional T cells promoting division and survival of effector and memory populations and pS6, a marker for an active mTOR pathway and autophagy detection. The understanding of the role of autophagy as a further mechanism underlying lymphocytes stability may open new therapeutic avenues for atherosclerosis

SIRT5 Inhibition Induces Brown Fat-Like Phenotype in 3T3-L1 Preadipocytes

Brown adipose tissue (BAT) activity plays a key role in regulating systemic energy. The activation of BAT results in increased energy expenditure, making this tissue an attractive pharmacological target for therapies against obesity and type 2 diabetes. Sirtuin 5 (SIRT5) affects BAT function by regulating adipogenic transcription factor expression and mitochondrial respiration. We analyzed the expression of SIRT5 in the different adipose depots of mice. We treated 3T3-L1 preadipocytes and mouse primary preadipocyte cultures with the SIRT5 inhibitor MC3482 and investigated the effects of this compound on adipose differentiation and function. The administration of MC3482 during the early stages of differentiation promoted the expression of brown adipocyte and mitochondrial biogenesis markers. Upon treatment with MC3482, 3T3-L1 adipocytes showed an increased activation of the AMP-activated protein kinase (AMPK), which is known to stimulate brown adipocyte differentiation. This effect was paralleled by an increase in autophagic/mitophagic flux and a reduction in lipid droplet size, mediated by a higher lipolytic rate. Of note, MC3482 increased the expression and the activity of adipose triglyceride lipase, without modulating hormone-sensitive lipase. Our findings reveal that SIRT5 inhibition stimulates brown adipogenesis in vitro, supporting this approach as a strategy to stimulate BAT and counteract obesity

Altered tregs differentiation and impaired autophagy correlate to atherosclerotic disease

Atherosclerosis is a progressive vascular disease representing the primary cause of morbidity and mortality in developed countries. Formerly, atherosclerosis was considered as a mere passive accumulation of lipids in blood vessels. However, it is now clear that atherosclerosis is a complex and multifactorial disease, in which the involvement of immune cells and inflammation play a key role. A variety of studies have shown that autophagy—a cellular catalytic mechanism able to remove injured cytoplasmic components in response to cellular stress—may be proatherogenic. So far, in this context, its role has been investigated in smooth muscle cells, macrophages, and endothelial cells, while the function of this catabolic protective process in lymphocyte functionality has been overlooked. The few studies carried out so far, however, suggested that autophagy modulation in lymphocyte subsets may be functionally related to plaque formation and development. Therefore, in this research, we aimed at better clarifying the role of lymphocyte subsets, mainly regulatory T cells (Tregs), in human atherosclerotic plaques and in animal models of atherosclerosis investigating the contribution of autophagy on immune cell homeostasis. Here, we investigate basal autophagy in a mouse model of atherosclerosis, apolipoprotein E (ApoE)-knockout (KO) mice, and we analyze the role of autophagy in driving Tregs polarization. We observed defective maturation of Tregs from ApoE-KO mice in response to tumor growth factor-β (TGFβ). TGFβ is a well-known autophagy inducer, and Tregs maturation defects in ApoE-KO mice seem to be related to autophagy impairment. In this work, we propose that autophagy underlies Tregs maturation, advocating that the study of this process in atherosclerosis may open new therapeutic strategie