Chromogranin A knockout (Chga-KO) mice exhibit enhanced insulin sensitivity despite obesity. Here, we probed the role of the chromogranin A-derived peptide pancreastatin (PST: CHGA ) by investigating the effect of diet-induced obesity (DIO) on insulin sensitivity of these mice. We found that on a high-fat diet (HFD), Chga-KO mice (KO-DIO) remain more insulin sensitive than wild-type DIO (WT-DIO) mice. Concomitant with this phenotype is enhanced Akt and AMPK signaling in muscle and white adipose tissue (WAT) as well as increased FoxO1 phosphorylation and expression of mature Srebp-1c in liver and downregulation of the hepatic gluconeogenic genes, Pepck and G6pase. KO-DIO mice also exhibited downregulation of cytokines and proinflammatory genes and upregulation of anti-inflammatory genes in WAT, and peritoneal macrophages from KO mice displayed similarly reduced proinflammatory gene expression. The insulin-sensitive, anti-inflammatory phenotype of KO-DIO mice is masked by supplementing PST. Conversely, a PST variant peptide PSTv1 (PST-ND3: CHGA 276-301 ), lacking PST activity, simulated the KO phenotype by sensitizing WT-DIO mice to insulin. In summary, the reduced inflammation due to PST deficiency prevented the development of insulin resistance in KO-DIO mice. Thus, obesity manifests insulin resistance only in the presence of PST, and in its absence obesity is dissociated from insulin resistance.The chromogranin A (human CHGA/mouse Chga) proprotein (1-4) undergoes proteolysis and gives rise to bioactive peptides including the antihypertensive catestatin (CHGA 352-372 ) (5-8) and the diabetogenic pancreastatin (PST: CHGA 250-301 ) (9-12). We have shown that Chgadeficient mice (Chga-KO) are obese, hyperadrenergic, and hypertensive. They display elevated levels of circulating leptin and catecholamines but lower levels of interleukin (IL)-6 and Mcp-1 (11,13-16). Despite these abnormalities, Chga-KO mice exhibit enhanced insulin sensitivity (11), a phenotype masked by supplementing PST. PST regulates hepatic insulin signaling through conventional (c) PKC and Srebp-1c (11). Increased plasma PST levels in diabetic populations correlate with insulin resistance (10). Similarly, increased circulating levels of PST in diet-induced obesity (DIO) and db/ db mice are associated with insulin resistance. Despite high levels of plasma leptin and catecholamines, Chga-KO mice are obese owing to peripheral leptin and catecholamine resistance (17).Since normal chow diet (NCD)-fed Chga-KO mice displayed increased insulin sensitivity (11), we hypothesized that Chga-KO mice may be able to maintain insulin sensitivity when exposed to the dysglycemic stress of a highfat diet (HFD). The hallmarks of insulin resistance in DIO mice are obesity, hyperinsulinemia, and increased inflammation (18)(19)(20)(21)(22). Suppression of inflammation in DIO mice can improve insulin sensitivity (23-25). For example, rosiglitazone can improve inflammation and insulin sensitivity in DIO mice without reducing obesity significantly (23-25). Chga-KO mice are...

Hypertension is associated with inflammation and excessive production of catecholamines. Hypertensive patients have reduced plasma levels of CST (catestatin)—a bioactive cleavage product of the prohormone CgA (chromogranin A). In mouse models, hypertension symptoms can be reduced by administration of CST, but the role of CST in the regulation of cardiovascular function is unknown. In this study, we generated mice with KO (knockout) of the region of the CgA gene coding for CST (CST-KO) and found that CST-KO mice are not only hypertensive as predicted but also display left ventricular hypertrophy, have marked macrophage infiltration of the heart and adrenal gland, and have elevated levels of proinflammatory cytokines and catecholamines. Intraperitoneal injection with CST reversed these phenotypes, and ischemic preconditioning-induced cardioprotection was also abolished in CST-KO mice. Experiments with chlodronate depletion of macrophages and bone marrow transfer showed that macrophages produce CST and that the antihypertensive effects of CST are mediated, in part, via CST’s immunosuppression of macrophages as a form of feedback inhibition. The data thus implicate CST as a key autocrine attenuator of the cardiac inflammation in hypertension by reducing macrophage inflammation.

38Objective: Hypertension (HTN) is a global pandemic, affecting more than one billion people. 39Although catestatin (CST), a chromogranin A (CgA)-derived peptide, decreases blood pressure 40 (BP) in rodent models of HTN, the mechanisms underlying its hypotensive action is yet to be 41 established. Here we generated CST knockout (CST-KO) mice to pinpoint the mechanism of the 42 hypotensive action of CST. 44Methods and Results: CST-KO mice were hypertensive; their serum cytokines were elevated, 45 anti-inflammatory genes were downregulated, and their hearts showed marked infiltration with 46 macrophages. CST replenishment reversed all these phenotypes -it normalized BP, reduced 47 serum cytokines, upregulated anti-inflammatory genes, and reduced the cardiac infiltrates by 48 ~30%, as determined by FACS. Pre-conditioning-induced cardioprotection was also abolished in 49 CST-KO mice. We hypothesize that CST's anti-hypertensive and cardioprotective effects may be 50 caused by suppressed trafficking of macrophages to the heart and reduced inflammation. Such 51 cause-and-effect relationship is supported by the fact that CST-KO mice became normotensive 52 when they were depleted of macrophages using chlodronate, or when they received bone marrow 53 transplant from wild-type littermates. Mechanistically, cardiac tissue transcriptomes revealed 54 multiple altered gene expression programs in CST-KO mice that are commonly encountered in 55 human cardiomyopathies. Among others, a prominent reduction of Glo1 gene was seen in CST-56 KO mice; supplementation with CST increased it expression by >7-fold. Because Glo1 in 57 macrophages metabolizes methylglyoxal, an inflammatory agent whose accumulation promotes 58 vascular damage in HTN and T2DM, this could be one of the means by which CST attenuates 59 inflammation and improves cardiovascular health. Repletion of CST also improved glucose 60 metabolism and increased the surface area of mitochondrial cristae and decreased the secretion 61 of catecholamines; the latter explains the anti-hypertensive actions of CST. 63Conclusions: We conclude that the anti-hypertensive effects of CST is mediated at least in part 64 via CST's anti-inflammatory actions; in the absence of CST, macrophages are more reactive, they 65 infiltrate the heart and alter the ultrastructure, physiologic and molecular makeup of the 66 myocardium. These studies implicate CST as a key mediator of the observed crosstalk between 67 systemic and cardiac inflammation in HTN.68 69 70 71 3 Abbreviations 72 2DG: 2-deoxy-glucose 73 Actc1: cardiac muscle actin alpha 74 Atp5j: mitochondrial ATP synthase subunit F6 75 BRS: baroreflex sensitivity 76 Cd36: cluster of differentiation 36 77 Cers2: ceramide synthase 2 78 CgA: chromogranin A 79 CST: catestatin 80 CST-KO: CST knockout Introduction 122 123 Hypertension (HTN) is an important risk factor for cardiovascular disease (CVD) and mortality 1 .124 The burden of HTN and the estimated HTN-associated deaths have increased substantially over 125 the past 25 years 2 .126 The role o...

In adolescence, health status is influenced by several factors, including dietary pattern and physical activity (PA) which are crucial elements of lifestyle in terms of prevention and treatment of metabolic and chronic diseases. The current study aimed to explore the impact of the different intensity levels of PA along with the adherence to a Mediterranean diet (MD), on body composition indices and metabolic parameters in a cohort of adolescents, thereby investigating potential predictors of health behavior in youth. This cross-sectional study was carried out among 92 participants (44 girls and 48 boys, aged 14 to 17 years), which were divided into the following three groups according to intensity levels of PA: Group A (physical inactivity), Group B (moderate PA), and Group C (vigorous-intensity PA). The Questionnaire of Adherence to the Mediterranean Diet (KIDMED test) was used to assess both diet composition and adherence to a MD. All subjects underwent anthropometric measurements, bio-impedentiometric analysis for body composition parameters, and biochemical and hormonal measurements. The majority of adolescents (60.87%) had a medium adherence to the MD, and even a better distribution of food rates was found in adolescents performing vigorous-intensity PA. A comparison of anthropometric measurements and body composition parameters among groups showed that body mass index and fat mass (FM) were significantly lower while body cell mass (BCM), free fat mass (FFM), phase angle (PhA), and total body water (TBW) were higher in Group C adolescents as compared with those of Group A. In Group C, insulin resistance (HOMA-IR) was reduced and insulin levels were inversely associated with FFM (r = −0.454 and p = 0.004) and directly correlated with FM (r = 0.331 and p = 0.003). In the same Group C, we observed elevated serum irisin levels and lower lipid profile markers as compared with Group A. Interestingly, irisin negatively correlated with both total cholesterol (r = −0.428 and p = 0.04) and LDL (r = −0.468 and p = 0.02) in Group C. Finally, a receiver operator characteristic curve (ROC) analysis revealed irisin, LDL, HDL, and body composition variables (FFM, BMC, PhA, and TBW) as the most predictive measures for vigorous-intensity PA. Our results highlight the importance of developing healthy lifestyle programs that include improving the intensity of PA among a young population as a superior strategy for ensuring a better quality of life.

Background Gut microbiota is implied in obesity, because of its ability to harvest energy from diet, and in the regulation of behavior. Given the link between gut microbiota, body composition, obesity, and anxiety, the aim of this study was to evaluate the effects of a new psychobiotic formulation. Methods Eligible patients were randomly divided into three groups: psychobiotics oral suspension group (POSG); dietary treatment group (DTG); combined treatment group (CTG). All subjects underwent body composition and psychological profile evaluation. Results Significant changes in body composition parameters in each group were relieved after all treatments. Hamilton anxiety rating scale (HAM-A) highlighted a significant reduction of the total score for all study population after treatments in POSG (p = 0.01) and CTG (p = 0.04). A reduction of HAM-A total score in anxious subjects in POSG or CTG and a significant reduction of positive subjects for HAM-A in POSG (p = 0.03) and in CDG (p = 0.01) were shown. Discussion Three-week intake of selected POS represents a good approach to solve problems related to obesity and behavior disorders. However, new clinical trials need to be performed on a larger population and for a longer period of treatment before definitive conclusions can be made. This trial is registered with NCT01890070.

The spread of the novel human respiratory coronavirus (SARS-CoV-2) is a global public health emergency. There is no known successful treatment as of this time, and there is a need for medical options to mitigate this current epidemic. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and is primarily trophic for the lower and upper respiratory tract. A number of current studies on COVID-19 have demonstrated the substantial increase in pro-inflammatory factors in the lungs during infection. The virus is also documented in the central nervous system and, particularly in the brainstem, which plays a key role in respiratory and cardiovascular function. Currently, there are few antiviral approaches, and several alternative drugs are under investigation. Two of these are Idelalisib and Ebastine, already proposed as preventive strategies in airways and allergic diseases. The interesting and evolving potential of phosphoinositide 3-kinase δ (PI3Kδ) inhibitors, together with Ebastine, lies in their ability to suppress the release of pro-inflammatory cytokines, such as IL-1β, IL-8, IL-6, and TNF-α, by T cells. This may represent an optional therapeutic choice for COVID-19 to reduce inflammatory reactions and mortality, enabling patients to recover faster. This concise communication aims to provide new potential therapeutic targets capable of mitigating and alleviating SARS-CoV-2 pandemic infection.

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