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

CXCL12 prolongs naive CD4 + T lymphocytes survival via activation of PKA, CREB and Bcl2 and BclXl up-regulation

Naive T lymphocytes recirculate through the body, traveling from secondary lymphoid organs through tissues and via lymphatic vessels and peripheral blood into other secondary lymphoid organs and into the bone marrow. In these tissues, lymphocytes are exposed to the chemokine CXCL12 which is abundantly produced in bone marrow and in lymph nodes by stromal cells. CXCL12 is known to drive lymphocytes chemotaxis and, in cells types such as stem cells, an antiapopototic effect has been described. Methods Here we analyzed the effect of CXCL12 exposure on naïve CD4 + T lymphocytes purified from peripheral blood by immunomagnetic negative isolation and cultured in a nutrient poor medium. We also studied, mainly by western blot analysis, the signaling pathways involved in CXCL12 action on naïve CD4 + T lymphocytes. Results We found that CXCL12-exposed cells survived longer than untreated ones and this prolonged lifespan was specific for resting naïve lymphocytes, while in vitro activated lymphoblasts died rapidly despite CXCL12 treatment. We demonstrated that the increased percentage of living cells observed upon CXCL12 administration was not due to induction of proliferation but to a prosurvival effect of this chemokine. Moreover, our data suggest that this prosurvival effect on naïve CD4 + T lymphocytes might likely be mediated by PKA-dependent CREB activation and consequent increased expression of the antiapoptotic factors Bcl2 and BclXl. Conclusions This newly reported activity of CXCL12 might contribute to the maintenance of the naïve T lymphocytes pool in vivo, which is needed to ensure a proper immune response to new antigens

Lipid peroxidation and total antioxidant capacity in vitreous, aqueous humor, and blood samples from patients with diabetic retinopathy

PurposeTo evaluate levels of malondialdehyde and the total antioxidant capacity (TAC) in the blood, aqueous humor, and vitreous bodies of diabetic and nondiabetic patients. We also measured the blood energy charge potential (ECP).MethodsWe examined 19 patients with type 2 diabetes mellitus and diabetic retinopathy. Ten were scheduled for cataract surgery and pars plana vitrectomy because of proliferative diabetic retinopathy (PDR). The other nine, with mild nonproliferative PDR (NPDR), and fourteen nondiabetic, age-matched subjects enrolled as a control group were scheduled for cataract surgery and vitrectomy because of epiretinal membranes. Blood, aqueous humor and vitreous body samples were collected at the time of surgery. Malondialdehyde concentrations and blood ECP were measured with high-performance liquid chromatography. The TAC of the samples was estimated with the oxygen radical absorbance capacity method.ResultsThe level of blood and vitreous malondialdehyde in the PDR group was significantly higher compared to controls and to NPDR patients. PDR patients also had lower levels of TAC at the vitreous body and aqueous humor level, but not at the blood level, compared to controls and with NPDR patients. In all diabetic patients, the blood ECP values were significantly lower, compared to control subjects.ConclusionsOur data support the hypothesis that oxidative stress and the decrease of antioxidant defenses are associated with the progression of diabetic retinopathy to its proliferative form. Antioxidant supply may have the effect of correcting oxidative stress and inhibiting disease progression

BNT162b2 mRNA COVID-19 vaccine does not impact the honeymoon phase in type 1 diabetes: a case report

Type 1 diabetes (T1D), which is caused by the autoimmune destruction of insulin-secreting pancreatic beta cells, represents a high-risk category requiring COVID-19 vaccine prioritization. Although COVID-19 vaccination can lead to transient hyperglycemia (vaccination-induced hyperglycemia; ViHG), its influence on the course of the clinical remission phase of T1D (a.k.a. "honeymoon phase") is currently unknown. Recently, there has been an increasing concern that COVID-19 vaccination may trigger autoimmune phenomena. We describe the case of a 24-year-old young Italian man with T1D who received two doses of the BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine during a prolonged honeymoon phase. He experienced a transient impairment in glucose control (as evidenced by continuous glucose monitoring) that was not associated with substantial changes in stimulated C-peptide levels and islet autoantibody titers. Nonetheless, large prospective studies are needed to confirm the safety and the immunometabolic impact of the BNT162b2 vaccine in T1D patients during the honeymoon phase. Thus far, T1D patients who are going to receive COVID-19 vaccination should be warned about the possible occurrence of transient ViHG and should undergo strict postvaccination surveillance

Health Effects of Red Wine Consumption: A Narrative Review of an Issue That Still Deserves Debate

A strong controversy persists regarding the effect of red wine (RW) consumption and health. Guidelines for the prevention of cardiovascular diseases (CVD) and cancers discourage alcohol consumption in any form, but several studies have demonstrated that low RW intake may have positive effects on CVD risk. This review evaluated randomised controlled trials (RCTs), examining the recent literature on the correlations between acute and chronic RW consumption and health. All RCTs published in English on PubMed from 1 January 2000 to 28 February 2023 were evaluated. Ninety-one RCTs were included in this review, seven of which had a duration of more than six months. We assessed the effect of RW on: (1) antioxidant status, (2) cardiovascular function, (3) coagulation pathway and platelet function, (4) endothelial function and arterial stiffness, (5) hypertension, (6) immune function and inflammation status, (7) lipid profile and homocysteine levels, (8) body composition, type 2 diabetes and glucose metabolism, and (9) gut microbiota and the gastrointestinal tract. RW consumption mostly results in improvements in antioxidant status, thrombosis and inflammation markers, lipid profile, and gut microbiota, with conflicting results on hypertension and cardiac function. Notably, beneficial effects were observed on oxidative stress, inflammation, and nephropathy markers, with a modest decrease in CVD risk in five out of seven studies that evaluated the effect of RW consumption. These studies were conducted mainly in patients with type 2 diabetes mellitus, and had a duration between six months and two years. Additional long-term RCTs are needed to confirm these benefits, and assess the potential risks associated with RW consumption

Nutraceuticals in Brown Adipose Tissue Activation

Obesity and its associated comorbidities have become pandemic, and challenge the global healthcare system. Lifestyle changes, nutritional interventions and phamaceuticals should be differently combined in a personalized strategy to tackle such a public health burden. Altered brown adipose tissue (BAT) function contributes to the pathophysiology of obesity and glucose metabolism dysfunctions. BAT thermogenic activity burns glucose and fatty acids to produce heat through uncoupled respiration, and can dissipate the excessive calorie intake, reduce glycemia and circulate fatty acids released from white adipose tissue. Thus, BAT activity is expected to contribute to whole body energy homeostasis and protect against obesity, diabetes and alterations in lipid profile. To date, pharmacological therapies aimed at activating brown fat have failed in clinical trials, due to cardiovascular side effects or scarce efficacy. On the other hand, several studies have identified plant-derived chemical compounds capable of stimulating BAT thermogenesis in animal models, suggesting the translational applications of dietary supplements to fight adipose tissue dysfunctions. This review describes several nutraceuticals with thermogenic properties and provides indications, at a molecular level, of the regulation of the adipocyte thermogenesis by the mentioned phytochemicals

Neutral Effect of Skeletal Muscle Mineralocorticoid Receptor on Glucose Metabolism in Mice

The mineralocorticoid receptor (MR) is able to regulate the transcription of a number of genes in the myotube, although its roles in skeletal muscle (SM) metabolism still await demonstration. SM represents a major site for glucose uptake, and its metabolic derangements play a pivotal role in the development of insulin resistance (IR). The aim of this study was to investigate the contribution of SM MR in mediating derangements of glucose metabolism in a mouse model of diet-induced obesity. We observed that mice fed a high-fat diet (HFD mice) showed impaired glucose tolerance compared to mice fed a normal diet (ND mice). Mice fed a 60% HFD treated with the MR antagonist Spironolactone (HFD + Spiro) for 12 weeks revealed an improvement in glucose tolerance, as measured with an intraperitoneal glucose tolerance test, compared with HFD mice. To investigate if blockade of SM MR could contribute to the favorable metabolic effects observed with pharmacological MR antagonism, we analyzed MR expression in the gastrocnemius, showing that SM MR protein abundance is downregulated by HFD compared to ND mice and that pharmacological treatment with Spiro was able to partially revert this effect in HFD + Spiro mice. Differently from what we have observed in adipose tissue, where HDF increased adipocyte MR expression, SM MR protein was down-regulated in our experimental model, suggesting a completely different role of SM MR in the regulation of glucose metabolism. To confirm this hypothesis, we investigated the effects of MR blockade on insulin signaling in a cellular model of IRin C2C12 myocytes, which were treated with or without Spiro. We confirmed MR protein downregulation in insulin-resistant myotubes. We also analyzed Akt phosphorylation upon insulin stimulation, and we did not observe any difference between palmitate- and palmitate + Spiro-treated cells. These results were confirmed by in vitro glucose uptake analysis. Taken together, our data indicate that reduced activity of SM MR does not improve insulin signaling in mouse skeletal myocytes and does not contribute to the favorable metabolic effects on glucose tolerance and IR induced by systemic pharmacological MR blockade

Exploring the Role of Skeletal Muscle in Insulin Resistance: Lessons from Cultured Cells to Animal Models

Skeletal muscle is essential to maintain vital functions such as movement, breathing, and thermogenesis, and it is now recognized as an endocrine organ. Muscles release factors named myokines, which can regulate several physiological processes. Moreover, skeletal muscle is particularly important in maintaining body homeostasis, since it is responsible for more than 75% of all insulin-mediated glucose disposal. Alterations of skeletal muscle differentiation and function, with subsequent dysfunctional expression and secretion of myokines, play a key role in the pathogenesis of obesity, type 2 diabetes, and other metabolic diseases, finally leading to cardiometabolic complications. Hence, a deeper understanding of the molecular mechanisms regulating skeletal muscle function related to energy metabolism is critical for novel strategies to treat and prevent insulin resistance and its cardiometabolic complications. This review will be focused on both cellular and animal models currently available for exploring skeletal muscle metabolism and endocrine function

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

VLCKD in Combination with Physical Exercise Preserves Skeletal Muscle Mass in Sarcopenic Obesity after Severe COVID-19 Disease: A Case Report

The prevalence of sarcopenic obesity is increasing worldwide, with a strong impact on public health and the national health care system. Sarcopenic obesity consists of fat depot expansion and associated systemic low-grade inflammation, exacerbating the decline in skeletal muscle mass and strength. Dietary approach and physical exercise represent essential tools for reducing body weight and preserving muscle mass and function in subjects with sarcopenic obesity. This case report describes the effects of a dietary intervention, based on a Very-Low-Calorie Ketogenic Diet (VLCKD) combined with physical exercise, on body composition, cardiometabolic risk factors, and muscle strength in a woman with sarcopenic obesity, two weeks after hospitalization for bilateral interstitial pneumonia due to COVID-19. To our knowledge, this is the first case report to describe the efficacy of a combined approach intervention including VLCKD along with physical exercise, in reducing fat mass, improving metabolic profile, and preserving skeletal muscle performance in a patient with obesity, soon after severe COVID-19 disease