Interleukin-16 is increased in obesity and alters adipogenesis and inflammation in vitro.

Introduction: Obesity is a chronic condition associated with low-grade inflammation mainly due to immune cell infiltration of white adipose tissue (WAT). WAT is distributed into two main depots: subcutaneous WAT (sWAT) and visceral WAT (vWAT), each with different biochemical features and metabolic roles. Proinflammatory cytokines including interleukin (IL)-16 are secreted by both adipocytes and infiltrated immune cells to upregulate inflammation. IL-16 has been widely studied in the peripheral proinflammatory immune response; however, little is known about its role in adipocytes in the context of obesity. Aim & Methods: We aimed to study the levels of IL-16 in WAT derived from sWAT and vWAT depots of humans with obesity and the role of this cytokine in palmitate-exposed 3T3-L1 adipocytes. Results: The results demonstrated that IL-16 expression was higher in vWAT compared with sWAT in individuals with obesity. In addition, IL-16 serum levels were higher in patients with obesity compared with normal-weight individuals, increased at 6 months after bariatric surgery, and at 12 months after surgery decreased to levels similar to before the intervention. Our in vitro models showed that IL-16 could modulate markers of adipogenesis (Pref1), lipid metabolism (Plin1, Cd36, and Glut4), fibrosis (Hif1a, Col4a, Col6a, and Vegf), and inflammatory signaling (IL6) during adipogenesis and in mature adipocytes. In addition, lipid accumulation and glycerol release assays suggested lipolysis alteration. Discussion: Our results suggest a potential role of IL-16 in adipogenesis, lipid and glucose homeostasis, fibrosis, and inflammation in an obesity context.

Claudin-1 as a novel target gene induced in obesity and associated to inflammation, fibrosis, and cell differentiation.

OBJECTIVE: T lymphocytes from visceral and subcutaneous white adipose tissues (vWAT and sWAT, respectively) can have opposing roles in the systemic metabolic changes associated with obesity. However, few studies have focused on this subject. Claudin-1 (CLDN1) is a protein involved canonically in tight junctions and tissue paracellular permeability. We evaluated T-lymphocyte gene expression in vWAT and sWAT and in the whole adipose depots in human samples. METHODS: A Clariom D-based transcriptomic analysis was performed on T lymphocytes magnetically separated from vWAT and sWAT from patients with obesity (Cohort 1; N = 11). Expression of candidate genes resulting from that analysis was determined in whole WAT from individuals with and without obesity (Cohort 2; patients with obesity: N = 13; patients without obesity: N = 14). RESULTS: We observed transcriptional differences between T lymphocytes from sWAT compared with vWAT. Specifically, CLDN1 expression was found to be dramatically induced in vWAT T cells relative to those isolated from sWAT in patients with obesity. CLDN1 was also induced in obesity in vWAT and its expression correlates with genes involved in inflammation, fibrosis, and adipogenesis. CONCLUSION: These results suggest that CLDN1 is a novel marker induced in obesity and differentially expressed in T lymphocytes infiltrated in human vWAT as compared with sWAT. This protein may have a crucial role in the crosstalk between T lymphocytes and other adipose tissue cells and may contribute to inflammation, fibrosis, and alter homeostasis and promote metabolic disease in obesity.

Transcriptional and epigenetic changes after dietary and surgical weight loss interventions in an animal model of obesity.

BACKGROUND: Identifying determinants that can predict response to weight loss interventions is imperative for optimizing therapeutic benefit. We aimed to identify changes in DNA methylation and mRNA expression of a subset of target genes following dietary and surgical interventions in high-fat-diet (HFD)-induced obese rats. METHODS: Forty-two adult Wistar Han male rats were divided into two groups: control rats (n = 7) and obese rats (n = 28), fed a HFD for 10 weeks (t10). Obese rats were randomly subdivided into five intervention groups (seven animals per group): (i) HFD; (ii) very-low-calorie diet (VLCD); (iii) sham surgery, and (iv) sleeve gastrectomy (SG). At week sixteen (t16), animals were sacrificed and tissue samples were collected to analyze changes in DNA methylation and mRNA expression of the selected genes. RESULTS: By type of intervention, the surgical procedures led to the greatest weight loss. Changes in methylation and/or expression of candidate genes occurred proportionally to the effectiveness of the weight loss interventions. Leptin expression, increased sixfold in the visceral fat of the obese rats, was partially normalized after all interventions. The expression of fatty acid synthase (FASN) and monocyte chemoattractant protein 1 (MCP-1) genes, which was reduced 0.5- and 0.15-fold, respectively, in the liver tissue of obese rats, were completely normalized after weight loss interventions, particularly after surgical interventions. The upregulation of FASN and MCP-1 gene expression was accompanied by a significant reduction in promoter methylation, up to 0.5-fold decrease in the case of the FASN (all intervention groups) and a 0.8-fold decrease in the case of the MCP-1 (SG group). CONCLUSIONS: Changes in tissue expression of specific genes involved in the pathophysiological mechanisms of obesity can be significantly attenuated following weight loss interventions, particularly surgery. Some of these genes are regulated by epigenetic mechanisms.

Implementation of a same-day discharge bariatric surgery program and follow-up with a telemonitoring platform.

INTRODUCTION: Some groups have initiated outpatient bariatric surgery programs in selected patients, publishing good results after sleeve gastrectomy. Recent studies show that outpatient surgery is also feasible and safe in Roux-en-Y gastric bypass. The aim of this paper is to describe and analyze the results of our initial experience after the implementation of a same-day discharge bariatric surgery program using a telemonitoring system. METHODS: We have completed a prospective, observational study with 14 consecutive, selected patients undergoing primary bariatric surgery (sleeve gastrectomy or Roux-en-Y gastric bypass) at a single center from April 2021 to February 2023, with home follow-up using the REVITA® telemonitoring platform (HI Iberia, S.A.) and the Home Hospitalization Unit. RESULTS: From April 2021 to February 2023, 14 patients were selected for this program, which meant 7.3% of the total of 191 patients who underwent bariatric surgery during this period. Ten out of the 14 patients selected completed the circuit (71.4%), 4 of whom consulted the emergency department within the first 24 h (40%). There were no serious complications, readmissions or re-operations typical of bariatric surgery. The estimated savings per patient who completed the circuit was 762. CONCLUSION: Bariatric surgery without hospital admission is feasible and safe in selected patients using a telemonitoring platform and with the support of a home hospitalization unit.

Lipidome Profiling in Childhood Obesity Compared to Adults: A Pilot Study.

The objective is to assess the circulating lipidome of children with obesity before and after lifestyle intervention and to compare the data to the circulating lipidome of adults with obesity before and after bariatric surgery. Ten pediatric (PE) and thirty adult (AD) patients with obesity were prospectively recruited at a referral single center. The PE cohort received lifestyle recommendations. The AD cohort underwent bariatric surgery. Clinical parameters and lipidome were analyzed in serum before and after six months of metabolic intervention. The abundance of phosphatidylinositols in the PE cohort and phosphatidylcholines in the AD significantly increased, while O-phosphatidylserines in the PE cohort and diacyl/triacylglycerols in the AD decreased. Fifteen lipid species were coincident in both groups after lifestyle intervention and bariatric surgery. Five species of phosphatidylinositols, sphingomyelins, and cholesteryl esters were upregulated. Eight species of diacylglycerols, glycerophosphoglycerols, glycerophosphoethanolamines, and phosphatidylcholines were downregulated. Most matching species were regulated in the same direction except for two phosphatidylinositols: PI(O-36:2) and PI(O-34:0). A specific set of lipid species regulated after bariatric surgery in adult individuals was also modulated in children undergoing lifestyle intervention, suggesting they may constitute a core circulating lipid profile signature indicative of early development of obesity and improvement after clinical interventions regardless of individual age.

Differential Behavior of 25(OH)D and f25(OH)D3 in Patients with Morbid Obesity After Bariatric Surgery.

BACKGROUND: Total 25-OH-vitamin D (25(OH)D) levels are decreased in patients with obesity, but few data exist regarding free-vitamin D3 (f25(OH)D3) concentrations. We aimed to evaluate the effect of bariatric surgery on 25(OH)D and f25(OH)D3 in a cohort of patients with morbid obesity. METHODS: Twenty-four patients submitted to sleeve gastrectomy (SG) (mean age 48 years, body mass index (BMI) 48.16±10.73k/m2) were evaluated before and 1 year after surgery. Anthropometric data, parathormone (PTH), calcium, alkaline phosphatase, 25(OH)D, and f25(OH)D3 were recorded. RESULTS: 25(OH)D and f25(OH)D3 correlated well before and after SG. Baseline determinations did not correlate with BMI, but they inversely correlated with BMI 1 year after surgery (rs=-0.46, p=0.02 and rs=-0.60, p=0.002, respectively). Post-surgery % total body weight loss (%TBWL) was 27.4±13.8 %; f25(OH)D3 concentrations increased significantly (5.28±2.29 pg/mL vs 6.64±2.25 pg/mL; p=0.03), whereas 25(OH)D did not change. Patients who achieved a BMI <35 kg/m2 1 year after surgery had significantly higher concentrations of f25(OH)D3 (7.9±1 pg/mL vs 4.8±1.1, p<0.001) and 25(OH)D (30.9±9.4 ng/mL vs 22.3±13.4; p=0.03) compared to those who remained with BMI >35 kg/m2. CONCLUSION: There is a significant inverse relationship between BMI and both f25(OH)D3 and 25(OH)D 1 year after surgery. Only f25(OH)D3 concentrations increased 1 year after surgery, which could be explained by a greater f25(OH)D3 sequestration before SG in the adipose tissue, potentially due to the more liposoluble nature of f25(OH)D3 than the protein-bound form 25(OH)D.

White adipose tissue-infiltrated CD11b+ myeloid cells are a source of S100A4, a new potential marker of hepatic damage.

CONTEXT: The endocrine and immunological properties of subcutaneous vs visceral adipose tissue (sWAT and vWAT, respectively) have turned a milestone in the study of metabolic diseases. The cytokine S100A4 is increased in obesity and has a role in adipose tissue dysfunction. However, the cellular source and its potential role in hepatic damage in obesity has not been elucidated. OBJECTIVE: We aim to study the regulation of S100A4 in immune cells present in sWAT and vWAT, as well as its potential role as a circulating marker of hepatic inflammation and steatosis. DESIGN: A cohort of 60 patients with obesity and distinct metabolic status was analyzed. CD11b+ myeloid cells and T cells were isolated from sWAT and vWAT by magnetic-activating cell sorting, and RNA was obtained. S100A4 gene expression was measured, and correlation analysis with clinical data was performed. Liver biopsies were obtained from 20 patients, and S100A4 circulating levels were measured to check the link with hepatic inflammation and steatosis. RESULTS: S100A4 gene expression was strongly upregulated in sWAT- vs vWAT-infiltrated CD11b+ cells, but this modulation was not observed in T cells. S100A4 mRNA levels from sWAT (and not from vWAT) CD11b+ cells positively correlated with glycemia, triglycerides, TNF-α gene expression and proliferation markers. Finally, circulating S100A4 directly correlated with liver steatosis and hepatic inflammatory markers. CONCLUSION: Our data suggest that sWAT-infiltrated CD11b+ cells could be a major source of S100A4 in obesity. Moreover, our correlations identify circulating S100A4 as a potential novel biomarker of hepatic damage and steatosis.

The chemokine CXCL14 is negatively associated with obesity and concomitant type-2 diabetes in humans.

Chemokine (C-X-C motif) ligand-14 (CXCL14) levels are downregulated in experimental rodent models of obesity. Moreover, CXCL14 reportedly favors insulin sensitization in obese mice. Here we examined, for the first time, the role of CXCL14 in human obesity. We found that circulating levels of CXCL14 were decreased in patients with obesity and, especially, those with concomitant type-2 diabetes. CXCL14 levels were negatively associated with BMI and with indices of impaired glucose/insulin homeostasis. CXCL14 expression was decreased in subcutaneous adipose tissue from patients with obesity and type-2 diabetes. In adipose tissue, CXCL14 expression was negatively correlated with the expression of genes encoding pro-inflammatory molecules, and positively correlated with GLUT4 and adiponectin expression. In conclusion, obesity, and especially, concomitant type-2 diabetes are associated with abnormally decreased levels of CXCL14 in blood and impaired CXCL14 expression in adipose tissue. CXCL14 downregulation may be a novel biomarker of altered metabolism in obesity. CXCL14 also deserves further research as a therapeutic candidate.

Differential association between S100A4 levels and insulin resistance in prepubertal children and adult subjects with clinically severe obesity.

OBJECTIVES: S100A4 has been recently identified as an adipokine associated with insulin resistance (IR) in adult subjects with obesity. However, no data about its levels in children with obesity and only a few approaches regarding its potential mechanism of action have been reported. To obtain a deeper understanding of the role of S100A4 in obesity, (a) S100A4 levels were measured in prepubertal children and adult subjects with and without obesity and studied the relationship with IR and (b) the effects of S100A4 in cultured human adipocytes and vascular smooth muscle cells (VSMCs) were determined. METHODS: Sixty-five children (50 with obesity, age 9.0 ±1.1 years and 15 normal weight, age 8.4 ±0.8 years) and fifty-nine adults (43 with severe obesity, age 46 ±11 years and 16 normal weight, age 45 ±9 years) were included. Blood from children and adults and adipose tissue samples from adults were obtained and analysed. Human adipocytes and VSMC were incubated with S100A4 to evaluate their response to this adipokine. RESULTS: Circulating S100A4 levels were increased in both children (P = .002) and adults (P < .001) with obesity compared with their normal-weight controls. In subjects with obesity, S100A4 levels were associated with homeostatic model assessment-insulin resistance (HOMA-IR) in adults (ßstd = .42, P = .008) but not in children (ßstd = .12, P = .356). Human adipocytes were not sensitive to S100A4, while incubation with this adipokine significantly reduced inflammatory markers in VSMC. CONCLUSIONS: Our human data demonstrate that higher S100A4 levels are a marker of IR in adults with obesity but not in prepubertal children. Furthermore, the in vitro results suggest that S100A4 might exert an anti-inflammatory effect. Further studies will be necessary to determine whether S100A4 can be a therapeutic target for obesity.

Use of Infrared Thermography to Estimate Brown Fat Activation After a Cooling Protocol in Patients with Severe Obesity That Underwent Bariatric Surgery.

BACKGROUND: In contrast to the energy-storing role of white adipose tissue (WAT), brown adipose tissue (BAT) acts as the main site of non-shivering thermogenesis in mammals and has been reported to play a role in protection against obesity and associated metabolic alterations in rodents. Infrared thermography (IRT) has been proposed as a novel non-invasive, safe, and quick method to estimate BAT thermogenic activation in humans. The aim of this study is to determine whether the IRT could be a potential new tool to estimate BAT thermogenic activation in patients with severe obesity in response to bariatric surgery. METHODS: Supraclavicular BAT thermogenic activation was evaluated using IRT in a cohort of 31 patients (50 ± 10 years old, BMI = 44.5 ± 7.8; 15 undergoing laparoscopy sleeve gastrectomy and 16 Roux-en-Y gastric bypass) at baseline and 6 months after a bariatric surgery. Clinical parameters were determined at these same time points. RESULTS: Supraclavicular BAT-related activity was detected in our patients by IRT after a cooling stimulus. The BAT thermogenic activation was higher at 6 months after laparoscopy sleeve gastrectomy (0.06 ± 0.1 vs 0.32 ± 0.1), while patients undergoing to a roux-en-Y gastric bypass did not change their thermogenic response using the same cooling stimulus (0.09 ± 0.1 vs 0.08 ± 0.1). CONCLUSIONS: Our study postulates the IRT as a potential tool to evaluate BAT thermogenic activation in patients with obesity before and after a bariatric surgery. Further studies are needed to evaluate differences between LSG technique and RYGB on BAT activation.

Laparoscopic sleeve gastrectomy induces molecular changes in peripheral white blood cells.

BACKGROUND & AIMS: Peripheral white blood cells (PWBC) may allow for the development of obesity biomarkers. We aimed to investigate the existence of gene expression and DNA methylation changes in PWBC after a very low calorie diet (VLCD) followed by a laparoscopic sleeve gastrectomy (LSG), and its correlation with surgical outcomes. METHODS: From July 2013 to June 2014, 35 consecutive bariatric patients and 33 healthy lean volunteers were recruited. Molecular data was obtained once on the control group and at 3 different times on the LSG group: 1) at baseline; 2) after 2 weeks of VLCD, right before LSG; and 3) 6 months after LSG. The expression of 12 genes in PWBC was analyzed by quantitative real-time polymerase chain reaction: ghrelin (GHRL), visfatin (NAMPT), insulin receptor substrate 1 (IRS1), fat mass and obesity-related gene (FTO), leptin (LEP), peroxisome proliferator-activated receptor gamma (PPARG), adiponectin (ADIPOQ), fatty acid synthase (FASN), melanocortin 4 receptor (MC4R), fas cell surface death receptor (FAS), tumor necrosis factor alpha (TNF) and chemokine (C-C motif) ligand 2 (CCL2). Moreover, DNA methylation of GHRL, NAMPT and FAS promoters was analyzed in PWBC by bisulfite pyrosequencing. RESULTS: Seven genes (GHRL, NAMPT, IRS1, FTO, FAS, TNF and CCL2) had detectable expression in PWBC. FTO expression at baseline was lower in patients than in controls (p = 0.042), equalizing after LSG. In patients, FAS expression decreased after VLCD (p = 0.01) and stayed low after LSG (p = 0.015). Also, CCL2 expression decreased 50% after LSG compared to pre-surgical levels (p = 0.016). All studied CpG sites in the GHRL gene promoter followed a consistent pattern of DNA methylation/demethylation. No direct correlation between these molecular changes and surgical outcomes was found at 1-year follow-up. CONCLUSIONS: FTO expression increased and FAS and CCL2 expression decreased in PWBC after LSG. Molecular changes did not correlate with surgical outcomes.

A Role for Oncostatin M in the Impairment of Glucose Homeostasis in Obesity.

CONTEXT: Oncostatin M (OSM) plays a key role in inflammation, but its regulation and function during obesity is not fully understood. OBJECTIVE: The aim of this study was to evaluate the relationship of OSM with the inflammatory state that leads to impaired glucose homeostasis in obesity. We also assessed whether OSM immunoneutralization could revert metabolic disturbances caused by a high-fat diet (HFD) in mice. DESIGN: 28 patients with severe obesity were included and stratified into two groups: (1) glucose levels <100 mg/dL and (2) glucose levels >100 mg/dL. White adipose tissue was obtained to examine OSM gene expression. Human adipocytes were used to evaluate the effect of OSM in the inflammatory response, and HFD-fed C57BL/6J mice were injected with anti-OSM antibody to evaluate its effects. RESULTS: OSM expression was elevated in subcutaneous and visceral fat from patients with obesity and hyperglycemia, and correlated with Glut4 mRNA levels, serum insulin, homeostatic model assessment of insulin resistance, and inflammatory markers. OSM inhibited adipogenesis and induced inflammation in human adipocytes. Finally, OSM receptor knockout mice had increased Glut4 mRNA levels in adipose tissue, and OSM immunoneutralization resulted in a reduction of glucose levels and Ccl2 expression in adipose tissue from HFD-fed mice. CONCLUSIONS: OSM contributes to the inflammatory state during obesity and may be involved in the development of insulin resistance.

Elevated Levels of Circulating miR-92a Are Associated with Impaired Glucose Homeostasis in Patients with Obesity and Correlate with Metabolic Status After Bariatric Surgery.

INTRODUCTION: miRNAs are small non-coding RNAs, some of which are expressed in adipose tissues, are present in the circulation, and are regulated in obesity. Bariatric surgery (BS) has been proposed to lead to activation of brown adipose tissue, an effect that may be related to beneficial effects of BS on systemic metabolism. Here, we evaluated circulating levels of miR-92a and miR-99b, two miRNAs proposed as biomarkers of brown fat activity, in a cohort of patients with severe obesity before and after BS, and studied their potential relationship with BS-associated improvements in metabolic parameters. METHODS: Circulating levels of miR-92a and miR-99b were quantified in a cohort of 26 patients (age, 48 ± 10 years; BMI, 45 ± 7 kg/m2) before and 6 months after BS. Clinical parameters were determined at different time points and correlations among them were studied. RESULTS: Basal levels of miR-92a were significantly increased in patients with obesity relative to lean controls. Serum miR-92a levels were strongly reduced at 6 months after BS, reaching levels similar to those in controls. Serum miR-99b levels were unchanged in relation to both the obese condition and BS. Elevated levels of miR-92a were directly correlated with worsened glucose homeostasis parameters and poor BS outcome. CONCLUSIONS: Our findings show that miR-92a is elevated in conditions of obesity, and its reduction after BS correlates with metabolic improvement. Further studies would be necessary to establish miR-92a as serum biomarker and potential predictor of the BS success in improving the metabolic status of patients with obesity.

Evaluation of Vitamin and Trace Element Requirements after Sleeve Gastrectomy at Long Term.

BACKGROUND: Nutritional deficiencies are common after bariatric surgery, but data are scarce after sleeve gastrectomy (SG) at long term. METHODS: We performed a prospective nutritional status evaluation before and at 2 and 5 years after SG in morbid obese patients receiving mulvitamin and mineral supplementation at a Spanish university hospital. One hundred seventy-six patients (49.3 ± 9.1 years and 46.7 ± 7.4 kg/m2) were evaluated; 51 of them were followed during 5 years. Anthropometric, compliance supplementation intake, and micronutrient evaluation were performed. RESULTS: Baseline concentrations were below normal values for 25(OH) vitamin D (73%), folic acid (16.5%), cobalamin (6.9%), pyridoxine (12%), thiamine (3.4%), and copper (0.5%). Anemia was found in 23%. In 49% of the subjects, at least one micronutrient deficiency was found at 2 years after SG. Vitamin D deficiency persisted at 2 and 5 years higher than 30% of patients. Frequencies of deficiencies for folic acid, B12, B6, and B1 vitamins decreased significantly after 2 years with normalization at 5 years. Copper deficiency increased between 1 and 2 years and it persisted at 5 years after SG. Vitamin supplementation compliance decreased progressively from the first year after surgery (94.8 to 81% at 2 years and to 53% 5 years after surgery). CONCLUSIONS: Vitamin D deficiency is the most prevalent long-term nutritional deficiency after SG. About half of patients show some micronutrient deficiency at medium long term, despite supplementation. A proactive follow-up is required to ensure a personalized and adequate supplementation in all surgically treated obese patients including those in which SG has been performed.

Baseline circulating ghrelin does not predict weight regain neither maintenance of weight loss after gastric bypass at long term.

BACKGROUND: Predictors of weight loss (WL) or weight regain (WR) after Roux-en-Y gastric bypass (RYGBP) are not established. The aim of this study was to analyze the usefulness of some baseline peptides (leptin, insulin, and ghrelin) as biomarkers of WL and WR in morbid obese patients after RYGBP at long term. METHODS: Seventy-six morbid obese (47 women, age 41.6 ± 9.6 years, body mass index [BMI] 52.1 ± 8 kg/m(2)) patients were evaluated at baseline and at 1, 2, and 6 years after surgery. RESULTS: Excess body weight loss after 6 years was of 63.9%. Age, BMI, and studied hormones at baseline or their changes over time did not predict long-term excess body weight loss. WR greater than 10% was observed in 36.8% of patients between 2 and 6 years of follow-up, but it was not correlated with BMI, age, or baseline peptide concentrations. CONCLUSION: Measurement of ghrelin, insulin, and leptin before surgery is not useful as predictors of WL or WR at long term after RYGBP.