Soluble P2X7 Receptor Plasma Levels in Obese Subjects before and after Weight Loss via Bariatric Surgery.

Obesity is a systemic disease frequently associated with important complications such as type 2 diabetes and cardiovascular diseases. It has also been proven that obesity is a disease associated with chronic low-grade systemic inflammation and that weight loss improves this low-grade chronic inflammatory condition. The P2X7 purinergic receptor (P2X7R), belonging to the family of the receptors for extracellular ATP, is a main player in inflammation, activating inflammasome and pro-inflammatory cytokine production. In this study, we evaluated the plasma levels of soluble P2X7R (sP2X7R) measured in a group of obese patients before and one year after bariatric surgery. Furthermore, we evaluated the relation of sP2X7R to inflammatory marker plasma levels. We enrolled 15 obese patients who underwent laparoscopic sleeve gastrectomy, evaluating anthropometric parameters (weight, height, BMI and waist circumference) before and after surgery. Moreover, we measured the plasma levels of inflammatory markers (CRP, TNFα and IL-6) before and after weight loss via bariatric surgery. The results of our study show that one year after bariatric surgery, obese patients significantly decrease body weight with a significant decrease in CRP, TNF-alfa and IL-6 plasma levels. Similarly, after weight loss, obese subjects showed a significant reduction in sP2X7R plasma levels. Moreover, before surgery, plasma levels of sP2X7R were inversely related with those of CRP, TNF-alfa and IL-6. Given the role of P2X7R in inflammation, we hypothesized that, in obese subjects, sP2X7R could represent a possible marker of chronic low-grade inflammation, hypothesizing a possible role as a mediator of obesity complications.

Non-aromatizable androgens modulate the lipopolysaccharide induced expression of the P2X7 receptor in human adipocytes.

Introduction: The activation of the P2X7 receptor subtype (P2X7R) has a main role in orchestrating the cellular inflammatory response in many different tissues. Obesity is characterized by dysfunctional fat deposition leading to a tissue-specific and systemic low-grade inflammation. Androgens and estrogens contribute to the whole adipose tissue inflammatory state, but the involvement of sex steroids in the purinergic signaling modulation in adipocytes is still unknown. Methods: We performed an in vitro study to evaluate the possible role of sex hormones on the P2X7R gene expression in human adipocytes, at baseline and after stimulation with bacterial lipopolysaccharide (LPS). We evaluated P2X7R gene expression during in vitro differentiation of human adipocytes, in the absence and presence of testosterone (T) and 17ß-estradiol (E2) in the presence and absence of LPS. Furthermore, we analyzed the effects of incubation with dihydrotestosterone (DHT), a non-aromatizable androgen, using the co-incubation of isolated human adipocytes with T alone or in combination with anastrozole, an inhibitor of aromatase, the enzyme responsible of T conversion to E2. Results: At baseline, incubation of adipocytes with T or E2 did not significantly affect P2X7R gene expression. On the contrary, the incubation with DHT was associated with a significant reduction of P2X7R gene expression. LPS incubation significantly increased gene expression of P2X7R with respect to baseline. Interestingly, after LPS stimulation, DHT exposure showed an additional effect, markedly increasing the P2X7R gene expression. This amplificatory effect was confirmed by the incubation of adipocytes to both anastrozole and testosterone. In these experimental conditions, while no effect was observed at baseline, an amplification of the expression of the P2X7R mRNA was observed after stimulation with LPS. Discussion: The purinergic system is involved in the inflammatory response of adipocytes, and androgens may modulate its activity. In particular DHT, a non-aromatizable androgen, amplifies the LPS-induced P2X7R gene expression in human adipocytes thus showing a gender regulated response of the expression of this purinergic receptor strongly involved in the inflammatory response in adipose tissue.

Body Weight Reduction by Bariatric Surgery Reduces the Plasma Levels of the Novel Orexigenic Gut Hormone Insulin-like Peptide 5 in Patients with Severe Obesity.

Insulin-like factor 5 (INSL5), a novel hormone secreted by the enteroendocrine cells of the distal colon, has been implicated in appetite and body weight regulation in animals given its orexigenic properties. We investigated basal INSL5 plasma levels in a group of morbidly obese subjects before and after laparoscopic sleeve gastrectomy. Furthermore, we analyzed the expression of INSL5 in human adipose tissue. Before bariatric surgery, obese subjects showed basal INSL5 plasma levels that were positively correlated with BMI, fat mass, and leptin plasma levels. After weight loss by laparoscopic sleeve gastrectomy, INSL5 plasma levels in obese subjects were significantly lower than those observed before surgery. Finally, we did not detect any expression of the INSL5 gene in human adipose tissue, both at the mRNA and protein levels. The present data show that subjects with obesity have INSL5 plasma levels positively correlating with adiposity markers. After bariatric surgery, INSL5 plasma levels decreased significantly, and this decrease was not directly due to the loss of adipose tissue since this tissue does not express INSL5. Considering the orexigenic properties of INSL5, the reduction of its plasma levels after bariatric surgery in obese subjects could participate in the still unclear mechanisms leading to appetite reduction that characterize bariatric surgery procedures.

Analysis of Walking Economy after Sleeve Gastrectomy in Patients with Severe Obesity.

BACKGROUND: Obesity is associated with a higher energy cost of walking which affects activities of daily living. Bariatric surgery with sleeve gastrectomy (SG) has beneficial effects on weight loss and comorbidities. PURPOSE: The aim of this study was to analyze the impact of SG on walking economy in subjects with severe obesity. METHODS: This observational cohort study included all patients with morbid obesity who were considered suitable candidates for SG between June 2017 and June 2019. Each patient underwent an incremental cardiopulmonary exercise test on a treadmill (modified Bruce protocol) one month before and six months after SG. Data on the energy cost of walking were recorded during three protocol stages (stage 0-slow flat walking: speed 2.7 km/h, slope 0%; stage ½-slow uphill walking: speed 2.7 km/h, slope 5%; stage 1-fast uphill walking: speed 4.0 km/h, slope 8%). RESULTS: 139 patients with morbid obesity (78% women; age 44.1 ± 10.7 years; BMI 42.5 ± 4.7 kg/m2) were included in the study. At six months post-SG, patients presented with a significantly decreased body weight (-30.5 ± 17.2 kg; p < 0.05), leading to an average BMI of 31.6 ± 4.2 kg/m2. The net energy cost of walking (measured in J/m and J/kg/m) of the subjects was lower compared to pre-SG at all three protocol stages. This improvement was also confirmed when the subjects were grouped by gender and obesity classes. CONCLUSION: After a significant weight loss induced by SG, regardless of the severity of obesity and gender, patients exhibited a lower energy expenditure and an improved walking economy. These changes make it easier to perform daily routines and may facilitate an increase in physical activity.

Molecular and Pharmacological Evidence for the Expression of Multiple Functional P2 Purinergic Receptors in Human Adipocytes.

Extracellular ATP exerts important functions as an extracellular signaling molecule via the activation of specific P2 purinergic receptors (P2X and P2Y). We investigated the expression of the different P2 receptors and their possible functional activation in human adipocytes in primary culture. We performed molecular expression analysis of the P2 receptors in human mature adipocytes; examined their functional activation by different nucleotides evaluating [Ca2+]i modifications and IL-6 secretion, and determined the ability of adipocytes to release ATP in the extracellular medium. Human adipocytes express different P2X and P2Y receptors. Extracellular ATP elicited a rise in [Ca2+]i via the activation of P2X and P2Y receptor subtypes. Human adipocytes spontaneously released ATP in the extracellular medium and secreted IL-6 both at rest and after stimulation with ATP. This stimulatory effect of ATP on IL-6 secretion was inhibited by pre-incubation with apyrase, an ATP metabolizing enzyme. These results demonstrate that human adipocytes express different P2X and P2Y receptors that are functionally activated by extracellular nucleotides. Furthermore, human adipocytes spontaneously release ATP, which can act in an autocrine/paracrine fashion on adipocytes, possibly participating in the regulation of inflammatory cytokine release. Thus, P2 purinergic receptors could be a potential therapeutic target to contrast the inflammatory and metabolic complications characterizing obesity.

EAES rapid guideline: systematic review, network meta-analysis, CINeMA and GRADE assessment, and European consensus on bariatric surgery-extension 2022.

BACKGROUND: The European Association for Endoscopic Surgery Bariatric Guidelines Group identified a gap in bariatric surgery recommendations with a structured, contextualized consideration of multiple bariatric interventions. OBJECTIVE: To provide evidence-informed, transparent and trustworthy recommendations on the use of sleeve gastrectomy, Roux-en-Y gastric bypass, adjustable gastric banding, gastric plication, biliopancreatic diversion with duodenal switch, one anastomosis gastric bypass, and single anastomosis duodeno-ileal bypass with sleeve gastrectomy in patients with severe obesity and metabolic diseases. Only laparoscopic procedures in adults were considered. METHODS: A European interdisciplinary panel including general surgeons, obesity physicians, anesthetists, a psychologist and a patient representative informed outcome importance and minimal important differences. We conducted a systematic review and frequentist fixed and random-effects network meta-analysis of randomized-controlled trials (RCTs) using the graph theory approach for each outcome. We calculated the odds ratio or the (standardized) mean differences with 95% confidence intervals for binary and continuous outcomes, respectively. We assessed the certainty of evidence using the CINeMA and GRADE methodologies. We considered the risk/benefit outcomes within a GRADE evidence to decision framework to arrive at recommendations, which were validated through an anonymous Delphi process of the panel. RESULTS: We identified 43 records reporting on 24 RCTs. Most network information surrounded sleeve gastrectomy and Roux-en-Y gastric bypass. Under consideration of the certainty of the evidence and evidence to decision parameters, we suggest sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass over adjustable gastric banding, biliopancreatic diversion with duodenal switch and gastric plication for the management of severe obesity and associated metabolic diseases. One anastomosis gastric bypass and single anastomosis duodeno-ileal bypass with sleeve gastrectomy are suggested as alternatives, although evidence on benefits and harms, and specific selection criteria is limited compared to sleeve gastrectomy and Roux-en-Y gastric bypass. The guideline, with recommendations, evidence summaries and decision aids in user friendly formats can also be accessed in MAGICapp:  https://app.magicapp.org/#/guideline/Lpv2kE CONCLUSIONS: This rapid guideline provides evidence-informed, pertinent recommendations on the use of bariatric and metabolic surgery for the management of severe obesity and metabolic diseases. The guideline replaces relevant recommendations published in the EAES Bariatric Guidelines 2020.

COVID-19 and smoking habits: a smoky situation!

Dear Editor, the issues recently raised by Carratù et al. on the role of smoking/former smoking in patients hospitalized for COVID-19 all around the world as widely reported in many different published papers, are important for different reasons...

Renal structure in type 2 diabetes: facts and misconceptions.

The clinical manifestations of diabetic nephropathy are similar in type 1 and type 2 diabetes, while the renal lesions may differ. Indeed, diabetic glomerulopathy is the predominant renal lesion in type 1 diabetes, although also tubular, interstitial and arteriolar lesions are present in the advanced stages of renal disease. In contrast, in type 2 diabetes renal lesions are heterogeneous, and a substantial number of type 2 diabetic patients with diabetic kidney disease have mild or absent glomerulopathy with tubulointerstitial and/or arteriolar abnormalities. In addition, a high prevalence of non-diabetic renal diseases, isolated or superimposed on classic diabetic nephropathy lesions have been reported in patients with type 2 diabetes, often reflecting the bias of selecting patients for unusual clinical presentations for renal biopsy. This review focuses on renal structural changes in type 2 diabetes, emphasizing the contribution of research kidney biopsy studies to the understanding of the pathogenesis of DKD and of the structural lesions responsible for the different clinical phenotypes. Also, kidney biopsies could provide relevant information in terms of renal prognosis, and help to understand the different responses to different therapies, especially SGLT2 inhibitors, thus allowing personalized medicine.

Clinical practice guidelines of the European Association for Endoscopic Surgery (EAES) on bariatric surgery: update 2020 endorsed by IFSO-EC, EASO and ESPCOP.

BACKGROUND: Surgery for obesity and metabolic diseases has been evolved in the light of new scientific evidence, long-term outcomes and accumulated experience. EAES has sponsored an update of previous guidelines on bariatric surgery. METHODS: A multidisciplinary group of bariatric surgeons, obesity physicians, nutritional experts, psychologists, anesthetists and a patient representative comprised the guideline development panel. Development and reporting conformed to GRADE guidelines and AGREE II standards. RESULTS: Systematic review of databases, record selection, data extraction and synthesis, evidence appraisal and evidence-to-decision frameworks were developed for 42 key questions in the domains Indication; Preoperative work-up; Perioperative management; Non-bypass, bypass and one-anastomosis procedures; Revisional surgery; Postoperative care; and Investigational procedures. A total of 36 recommendations and position statements were formed through a modified Delphi procedure. CONCLUSION: This document summarizes the latest evidence on bariatric surgery through state-of-the art guideline development, aiming to facilitate evidence-based clinical decisions.

The P2X7 Receptor and NLRP3 Axis in Non-Alcoholic Fatty Liver Disease: A Brief Review.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, and its prevalence is reaching epidemic characteristics both in adults and in children. The increase of NAFLD prevalence parallels that of obesity, now representing the major cause of liver inflammation, increasing the risk of cirrhosis and hepatocarcinoma. Furthermore, NAFLD is a risk factor for cardiovascular diseases and type 2 diabetes, two of the major leading causes of morbidity and mortality in western countries. Thus a significant amount of studies have dealt with the evaluation of the possible molecular mechanisms leading to NAFLD and its inflammatory consequences within the liver, the non-alcoholic steatohepatitis, and cirrhosis. The inflammasome is a key player in the inflammation and fibrogenic responses in many different tissues, including the liver. The activation of the NLRP3 inflammasome requires the activation by extracellular adenosine tri-phosphate (ATP) of a specific purinergic receptor named P2X7 located in the target cells, although other pathways have been described. To this regard, extracellular ATP acts as an internal danger signal coming from damaged cells participating in the activation of the inflammatory process, a signaling pathway common to many different tissues. Here, we briefly review the involvement of the P2X7 receptor/inflammasome NLRP3 axis in the pathophysiological events leading to NAFLD and its inflammatory and fibrotic evolutions, reporting the possible therapeutical strategies targeting the P2X7 receptor/NLRP3 inflammasome.

Effects of Surgical and Non-surgical Weight Loss on Migraine Headache: a Systematic Review and Meta-Analysis.

BACKGROUND: The aim of this study was to perform a meta-analysis on the effect of weight loss obtained by bariatric surgery or behavioral intervention on migraine frequency and indices of severity. MATERIALS AND METHODS: A search through Pubmed/Medline, ISI-web of knowledge, and Google Scholar retrieved 10 studies (n = 473). Selected outcomes were Headache Frequency, Pain Severity, Disability, and Attack Duration while BMI, BMI change, type of intervention (bariatric vs. behavioral), and type of population (adult vs. pediatric) were used for moderators and meta-regression analysis. RESULTS: Random effect meta-analysis shows that weight loss yields significant reductions in Headache Frequency (ES - 0.78, p < 0.0001), Pain Severity (ES - 1.04, p < 0.0001), Disability (ES -0.68, p < 0.0001), and Attack Duration (ES - 0.25, p = 0.017). Improvement in migraine was not correlated either to the degree of obesity at baseline or the degree of weight reduction. The effect on migraine was similar when weight reduction was obtained with bariatric surgery or behavioral intervention and was comparable in adult and pediatric populations. CONCLUSIONS: Weight loss improves characteristics of migraine headache in patients who have obesity independently of the type of intervention and the amount of weight loss. The mechanisms underlying the link between obesity, weight loss, and migraine headache may include chronic inflammation, obesity comorbidities, and overlapping behavioral and psychological risk factors.

Short-term effects of surgical weight loss after sleeve gastrectomy on sex steroids plasma levels and PSA concentration in men with severe obesity.

Male obesity is known to be associated with hypogonadism, which can be reverted after surgical weight reduction. However, the evidence about how rapidly this effect rises after surgery and what consequences each procedure have on prostate function and prostatic-specific antigen (PSA) concentration is scarce. So, we evaluated total testosterone, estradiol, luteinizing hormone, follicle-stimulating hormone and PSA plasma levels in a group of 29 Caucasian obese men (BMI - 43.4 ± 8.5 kg/m2) before and one month after sleeve gastrectomy. 19 lean healthy male subjects were considered as controls. As expected, obese patients showed a high prevalence of hypogonadism (51.6%) at baseline, with reduced total testosterone compared to lean controls (10.8 ± 3.5 vs 15.7 ± 4.2 nmol/l, p < .01), higher estradiol (124.4 ± 46.5 vs 78.7 ± 39.6 pmol/l, p < .01), lower luteinizing hormone and follicle stimulating hormone (3.6 ± 1.3 and 2.5 ± 0.9 vs 5.2 ± 2.4 and 5.9 ± 3.8 U/L, respectively, p < .05) plasma levels. One month after surgery, patients showed a significant body weight reduction (-17.2 ± 6.7 kg) with increased total testosterone (from 10.8 ± 3.5 to 18.9 ± 4.9 nmol/l, p < .001), reduced estradiol (from 124.4 ± 46.5 to 96.1 ± 34.3 pmol/l, p < .05) and increased PSA (from 0.74 ± 0.38 to 1.0 ± 0.51 µg/l, p < .001). These results confirm that hypogonadism is highly prevalent in obese males, but they also show that it can be early reversed after sleeve gastrectomy, further confirming the strong indication to surgery of hypogonadal patients with severely reduced quality of life. Higher testosterone levels may be responsible for the increase of PSA observed after surgery; however, PSA concentration has to be monitored over time to avoid underrating of potential severe prostate diseases.