Project description:Background: Low-density neutrophils (LDN) are increased in several inflammatory diseases, and may also play a role in low-grade chronic inflammation in obesity. Yet their role in obesity or the effect of bariatric surgery-induced weight loss is unknown. Methods: We compared circulating LDN, their function, and gene expression between morbidly obese patients (MOP; BMI > 40 Kg/m2) and normal-weight controls (NWC; BMI < 25 Kg/m2) in a case-control study. Additionally, in a prospective longitudinal study, we measure changes in the frequency of LDN before and after bariatric surgery, and tested possible associations with metabolic and inflammatory parameters. Findings: LDN and inflammatory markers were significantly increased in MOP (n=27) compared to NWC (n=20). Transcriptome analysis of LDN from MOP showed an increased neutrophil-related gene expression signature associated with inflammation, neutrophil activation, and immunosuppressive function. However, LDN did not suppress T cells proliferation and produced low levels of ROS. Circulating LDN in MOP significantly decreased after surgery in parallel with BMI, metabolic syndrome and inflammatory markers. Interpretation: Obesity increases LDN with inflammatory gene signature. Bariatric surgery has anti-inflammatory effect including reduction of LDN. Gene expression and phenotype suggest that LDN represent a neutrophil subset that may be associated with obesity-associated chronic inflammation that promotes co-morbidities.
Project description:Transcriptional profiling of subcutaneous adipose tissue before and after 2 years of bariatric surgery. This type of surgery produce a masive weight loss in morbidly obese subjects, and improve the comorbidities associated to obesity. Goal was to determine the effects of bariatric surgery on the gene expression of subcutaneous adipose tissue.
Project description:Obesity is associated with multiple diseases. Bariatric surgery is the most effective therapy for severe obesity that can reduce body weight and obesity-associated morbidity. The metabolic alterations associated with obesity and respective changes after bariatric surgery are incompletely understood.We comprehensively assessed metabolic alterations associated with severe obesity and distinct bariatric procedures. In our longitudinal observational study, we applied a (1)H-nuclear magnetic resonance-based global, untargeted metabolomics strategy on human serum samples that were collected before and repeatedly <=1 y after distinct bariatric procedures [i.e., a sleeve gastrectomy, proximal Roux-en Y gastric bypass (RYGB), and distal RYGB]. For comparison, we also analyzed serum samples from normal-weight and less-obese subjects who were matched for 1-y postoperative body mass index (BMI) values of the surgical groups. We identified a metabolomic fingerprint in obese subjects that was clearly discriminated from that of normal-weight subjects. Furthermore, we showed that bariatric surgery (sleeve gastrectomy and proximal and distal RYGB) dynamically affected this fingerprint in a procedure-dependent manner, thereby establishing new fingerprints that could be discriminated from those of BMI-matched and normal-weight control subjects. Metabolites that largely contributed to the metabolomic fingerprints of severe obesity were aromatic and branched-chain amino acids (elevated), metabolites related to energy metabolism (pyruvate and citrate; elevated), and metabolites suggested to be derived from gut microbiota (formate, methanol, and isopropanol; all elevated). Our data indicate that bariatric surgery, irrespective of the specific kind of procedure used, reverses most of the metabolic alterations associated with obesity and suggest profound changes in gut microbiome-host interactions after the surgery. This trial was registered at clinicaltrials.gov as NCT02480322.
Project description:Low-grade chronic inflammation plays an important role in the development of obesity and obesity-associated disorders such as insulin resistance, type 2 diabetes, the metabolic syndrome and atherosclerosis. One possible link between obesity and inflammation is the enhanced activation of circulating monocytes making them more prone to infiltration into the adipose and vascular tissues of obese persons. Furthermore, weight loss after bariatric surgery is associated with less inflammation. Transcriptome analysis of circulating monocytes from control and obese patients before and after bariatric surgery will potentially provide insights into the pathophysiology of obesity and associated disorders and supply biomarkers for diagnostic purpose. The cohort comprised 6 lean age-matched controls (BMI: 20.3±0.5 kg/m2, mean±SEM) and 18 obese individuals without clinical symptoms of cardiovascular disease (BMI: 45.1±1.4 kg/m2, P<0.001 compared with lean controls). These 18 morbidly obese subjects were referred to our hospital for bariatric surgery. Before they were included, individuals were evaluated by an endocrinologist, an abdominal surgeon, a psychologist and a dietician. Only after multidisciplinary deliberation, the selected patients received a laparoscopic Roux-en-Y gastric bypass. CD14+ monocytes were collected before and three months after bariatric surgery (BMI: 37.5±1.3 kg/m2, P<0.001 compared with before weight loss), total RNA was extracted and subjected to genome-wide expression analysis. Samples consisted of CD14+ monocytes from 6 lean controls and 18 morbidly obese patients before and three months after bariatric surgery. The 6 lean controls were also used to make 6 control pools.
Project description:Patients undergoing bariatric surgery are protected from subsequent breast cancer risk. It is unknown whether weight loss alone or surgery-specific alterations mediate risk reduction. We examined breast cancer in a pre-clinical model of diet induced obesity (DIO) followed by vertical sleeve gastrectomy (VSG) or dietary weight loss. DIO exacerbated tumor progression compared to lean controls, while VSG-induced weight loss reversed this exacerbation. However, dietary interventions were more effective than VSG despite similar reductions in weight and adiposity, potentially due to elevated immunosuppression after VSG. In tumor bearing mice, anti-PD-L1 immunotherapy after VSG improved anti-tumor immunity and potently impaired tumor progression. Thus, weight loss before tumor onset was protective regardless of intervention. Importantly, immunotherapy specifically improved outcomes in VSG.
Project description:Patients undergoing bariatric surgery are protected from subsequent breast cancer risk. It is unknown whether weight loss alone or surgery-specific alterations mediate risk reduction. We examined breast cancer in a pre-clinical model of diet induced obesity (DIO) followed by vertical sleeve gastrectomy (VSG) or dietary weight loss. DIO exacerbated tumor progression compared to lean controls, while VSG-induced weight loss reversed this exacerbation. However, dietary interventions were more effective than VSG despite similar reductions in weight and adiposity, potentially due to elevated immunosuppression after VSG. In tumor bearing mice, anti-PD-L1 immunotherapy after VSG improved anti-tumor immunity and potently impaired tumor progression. Thus, weight loss before tumor onset was protective regardless of intervention. Importantly, immunotherapy specifically improved outcomes in VSG.
Project description:Low-grade chronic inflammation plays an important role in the development of obesity and obesity-associated disorders such as insulin resistance, type 2 diabetes, the metabolic syndrome and atherosclerosis. One possible link between obesity and inflammation is the enhanced activation of circulating monocytes making them more prone to infiltration into the adipose and vascular tissues of obese persons. Furthermore, weight loss after bariatric surgery is associated with less inflammation. Transcriptome analysis of circulating monocytes from control and obese patients before and after bariatric surgery will potentially provide insights into the pathophysiology of obesity and associated disorders and supply biomarkers for diagnostic purpose. The cohort comprised 6 lean age-matched controls (BMI: 20.3±0.5 kg/m2, mean±SEM) and 18 obese individuals without clinical symptoms of cardiovascular disease (BMI: 45.1±1.4 kg/m2, P<0.001 compared with lean controls). These 18 morbidly obese subjects were referred to our hospital for bariatric surgery. Before they were included, individuals were evaluated by an endocrinologist, an abdominal surgeon, a psychologist and a dietician. Only after multidisciplinary deliberation, the selected patients received a laparoscopic Roux-en-Y gastric bypass. CD14+ monocytes were collected before and three months after bariatric surgery (BMI: 37.5±1.3 kg/m2, P<0.001 compared with before weight loss), total RNA was extracted and subjected to genome-wide expression analysis.
Project description:Bariatric surgery mediated weight loss has been shown to significantly reduce breast cancer incidence in women. We hypothesize that loss of excessive adiposity, reduces net Estrogen Receptor Alpha activation which in turn lowers breast cancer risk. A differential gene expression analysis and subsequent pathway enrichment analysis would reveal the relevant molecular mechanism behind the preventive effect of weight loss. We will correlate our RNASeq data findings with serum and breast tissue concentration of hormones as well as expression of proteins regulating hormone synthesis in breast. For this study, we recruited 30 patients who were prescribed baritaric surgery and met our selection criteria (no familial or personal history of breast cancer and free of other confounding conditions). Breast tissue and blood was collected at the day of surgery and at follow up after the patient lost 25% excess body weight. The breast core biopsy was preserved in RNALater till rna isolation and library preparation.