Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH.

BACKGROUND & AIMS: In non-alcoholic fatty liver disease (NAFLD), monocytes infiltrate visceral adipose tissue promoting local and hepatic inflammation. However, it remains unclear what drives inflammation and how the immune landscape in adipose tissue differs across the NAFLD severity spectrum. We aimed to assess adipose tissue macrophage (ATM) heterogeneity in a NAFLD cohort. METHODS: Visceral adipose tissue macrophages from lean and obese patients, stratified by NAFLD phenotypes, underwent single-cell RNA sequencing. Adipose tissue vascular integrity and breaching was assessed on a protein level via immunohistochemistry and immunofluorescence to determine targets of interest. RESULTS: We discovered multiple ATM populations, including resident vasculature-associated macrophages (ResVAMs) and distinct metabolically active macrophages (MMacs). Using trajectory analysis, we show that ResVAMs and MMacs are replenished by a common transitional macrophage (TransMac) subtype and that, during NASH, MMacs are not effectively replenished by TransMac precursors. We postulate an accessory role for MMacs and ResVAMs in protecting the adipose tissue vascular barrier, since they both interact with endothelial cells and localize around the vasculature. However, across the NAFLD severity spectrum, alterations occur in these subsets that parallel an adipose tissue vasculature breach characterized by albumin extravasation into the perivascular tissue. CONCLUSIONS: NAFLD-related macrophage dysfunction coincides with a loss of adipose tissue vascular integrity, providing a plausible mechanism by which tissue inflammation is perpetuated in adipose tissue and downstream in the liver. IMPACT AND IMPLICATIONS: Our study describes for the first time the myeloid cell landscape in human visceral adipose tissue at single-cell level within a cohort of well-characterized patients with non-alcoholic fatty liver disease. We report unique non-alcoholic steatohepatitis-specific transcriptional changes within metabolically active macrophages (MMacs) and resident vasculature-associated macrophages (ResVAMs) and we demonstrate their spatial location surrounding the vasculature. These dysfunctional transcriptional macrophage states coincided with the loss of adipose tissue vascular integrity, providing a plausible mechanism by which tissue inflammation is perpetuated in adipose tissue and downstream in the liver. Our study provides a theoretical basis for new therapeutic strategies to be directed towards reinstating the endogenous metabolic, homeostatic and cytoprotective functions of ResVAMs and MMacs, including their role in protecting vascular integrity.

Change in carbohydrate intake one year after Roux-en-Y gastric bypass: A prospective study.

Background and objectives: To investigate the effect of carbohydrate intake before laparoscopic Roux-en-Y gastric bypass (LRYGB) on body weight, body composition and glycaemic status after surgery. Methods: In a tertiary centre cohort study, dietary habits, body composition and glycaemic status were evaluated before and 3, 6 and 12 months after LRYGB. Detailed dietary food records were processed by specialized dietitians on the basis of a standard protocol. The study population was subdivided according to relative carbohydrate intake before surgery. Results: Before surgery, 30 patients had a moderate relative carbohydrate intake (26%-45%, M-CHO), a mean body mass index (BMI) of 40.4 ± 3.9 kg/m² and a mean glycated haemoglobin A1c (A1C) of 6.5 ± 1.2% compared to 20 patients with a high relative carbohydrate intake (> 45%, H-CHO), mean BMI of 40.9 ± 3.7 kg/m² (non-significant, NS) and a mean A1C of 6.2% (NS). One year after surgery, body weight, body composition and glycaemic status were similar in the M-CHO (n = 25) and H-CHO groups (n = 16), despite less caloric intake in the H-CHO group (1317 ± 285 g vs. 1646 ± 345 g in M-CHO, p < 0.01). Their relative carbohydrate intake converged to 46% in both groups, but the H-CHO group reduced the absolute total carbohydrate consumption more than the M-CHO group (190 ± 50 g in M-CHO vs. 153 ± 39 g in H-CHO, p < 0.05), and this was especially pronounced for the mono- and disaccharides (86 ± 30 g in M-CHO vs. 65 ± 27 g in H-CHO, p < 0.05). Conclusion: A high relative carbohydrate intake before LRYGB, did not influence the change in body composition or diabetes status after surgery, despite a significantly lower total energy intake and less mono- and disaccharide consumption after surgery.

Defining Global Benchmarks in Elective Secondary Bariatric Surgery Comprising Conversional, Revisional, and Reversal Procedures.

OBJECTIVE: To define "best possible" outcomes for secondary bariatric surgery (BS). BACKGROUND: Management of poor response and of long-term complications after BS is complex and under-investigated. Indications and types of reoperations vary widely and postoperative complication rates are higher compared to primary BS. METHODS: Out of 44,884 BS performed in 18 high-volume centers from 4 continents between 06/2013-05/2019, 5,349 (12%) secondary BS cases were identified. Twenty-one outcome benchmarks were established in low-risk patients, defined as the 75th percentile of the median outcome values of centers. Benchmark cases had no previous laparotomy, diabetes, sleep apnea, cardiopathy, renal insufficiency, inflammatory bowel disease, immunosuppression, thromboembolic events, BMI> 50 kg/m2 or age> 65 years. RESULTS: The benchmark cohort included 3143 cases, mainly females (85%), aged 43.8 ±â€Š10 years, 8.4 ±â€Š5.3 years after primary BS, with a BMI 35.2 ±â€Š7 kg/m2. Main indications were insufficient weight loss (43%) and gastro-esophageal reflux disease/dysphagia (25%). 90-days postoperatively, 14.6% of benchmark patients presented ≥1 complication, mortality was 0.06% (n = 2). Significantly higher morbidity was observed in non-benchmark cases (OR 1.37) and after conversional/reversal or revisional procedures with gastrointestinal suture/stapling (OR 1.84). Benchmark cutoffs for conversional BS were ≤4.5% re-intervention, ≤8.3% re-operation 90-days postoperatively. At 2-years (IQR 1-3) 15.6% of benchmark patients required a reoperation. CONCLUSION: Secondary BS is safe, although postoperative morbidity exceeds the established benchmarks for primary BS. The excess morbidity is due to an increased risk of gastrointestinal leakage and higher need for intensive care. The considerable rate of tertiary BS warrants expertise and future research to optimize the management of non-success after BS.

Late complications of biliopancreatic diversion in an older patient: a case report.

BACKGROUND: In the mid-seventies, biliopancreatic diversion became popular as weight-loss surgery procedure. This bariatric procedure combines distal gastric resection and intestinal malabsorption, leading to greater weight loss and improvement of co-morbidities than other bariatric procedures. Nowadays, biliopancreatic diversion has become obsolete due to the high risk of nutritional complications. However, current patients with biliopancreatic diversions are aging. Consequently, geriatricians and general practitioners will encounter them more often and will be faced with the consequences of late complications. CASE PRESENTATION: A 74-year old female presented with weakness, recurrent falls, confusion, episodes of irresponsiveness, anorexia and weight loss. Her medical history included osteoporosis, herpes encephalitis 8 years prior and a biliopancreatic diversion (Scopinaro surgery) at age 52. Cerebral imaging showed herpes sequelae without major atrophy. Delirium was diagnosed with underlying nutritional deficiencies. Biochemical screening indicated vitamin A deficiency, vitamin E deficiency, zinc deficiency and severe hypoalbuminemia. While thiamin level and fasting blood glucose were normal. However, postprandial hyperinsulinemic hypoglycemia was observed with concomitant signs of confusion and blurred consciousness. After initiating parenteral nutrition with additional micronutrient supplementation, a marked improvement was observed in cognitive and physical functioning. CONCLUSIONS: Long-term effects of biliopancreatic diversion remain relatively underreported in older patients. However, the anatomical and physiological changes of the gastrointestinal tract can contribute to the development of metabolic and nutritional complications that may culminate in cognitive impairment, functional decline and delirium. Therefore, it is warranted to evaluate the presence of metabolic disturbances and nutritional complications in older patients after biliopancreatic diversion.

The curious fate of bone following bariatric surgery: bone effects of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) in mice.

BACKGROUND: Bone loss and increased fracture risk following bariatric surgery has been reported. We investigated whether the two most commonly performed surgeries, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), lead to bone loss. In addition, we examined whether fortification of the diet with calcium citrate prevents bone loss. METHODS: We used mouse models for SG and RYGB and compared bone loss with a group of sham mice with similar weight loss. All groups were switched at the time of surgery to a low-fat diet (LFD). We also examined whether fortification of the diet with calcium citrate and vitamin D was able to prevent bone loss. RESULTS: At 2 weeks we observed no major bone effects. However, at 8 weeks, both trabecular and cortical bone were lost to the same extent after SG and RYGB, despite increased calcium absorption and adequate serum levels of calcium, vitamin D, and parathyroid hormone (PTH). Diet fortification with calcium citrate and vitamin D was able to partially prevent bone loss. CONCLUSIONS: Both SG and RYGB lead to excess bone loss, despite intestinal adaptations to increase calcium absorption. Fortifying the diet with calcium citrate and vitamin D partly prevented the observed bone loss. This finding emphasizes the importance of nutritional support strategies after bariatric surgery, but also affirms that the exact mechanisms leading to bone loss after bariatric surgery remain elusive and thus warrant further research.

Obesity alters adrenergic and chemosensory signaling pathways that regulate ghrelin secretion in the human gut.

Chemosensory signaling in organs such as the mouth and gut contributes to the mechanisms that control metabolism. We investigated the chemosensory pathways that regulate secretion of the hunger hormone ghrelin in response to neurotransmitters, bitter and sweet tastants at the cellular level in the human gut mucosa, and the disturbances in this regulatory pathway induced by obesity. Obesity impaired ghrelin protein production and adrenalin-induced ghrelin secretion in fundic cells, which was counterbalanced by somatostatin. Bitter agonists selective for taste receptor type 2 (TAS2Rs), TAS2R5 and TAS2R10 stimulated ghrelin secretion in fundic cells. The stimulatory effect of the broadly tuned bitter agonist, denatonium benzoate, was selectively blunted by obesity in the small intestine but not in the fundus. Luminal glucose concentrations inhibited ghrelin secretion via sodium-dependent glucose cotransporter and taste receptor type 1 member 3. Obesity altered the sensitivity of the ghrelin cell to glucose in the small intestine but not in the fundus. Sweet taste receptor activation inhibited bitter taste signaling of the ghrelin cell. In conclusion, obesity impairs the sympathetic drive that controls ghrelin release in the fundus and affects the sensitivity of the ghrelin cell to bitter and sweet stimuli in the small intestine but not in the fundus. Region-selective targeting of gut taste receptors in obesity is indicated.-Wang, Q., Liszt, K. I., Deloose, E., Canovai, E., Thijs, T., Farré, R., Ceulemans, L. J., Lannoo, M., Tack, J., Depoortere, I. Obesity alters adrenergic and chemosensory signaling pathways that regulate ghrelin secretion in the human gut.

Bariatric Surgery Does Not Appear to Affect Women's Breast-Milk Composition.

Background: The breast-milk composition in the first 6 wk postpartum of women who have undergone bariatric surgery (BS) is unknown. Objective: The aim of this study was to examine 1) the breast-milk macronutrient and vitamin A composition in women who had and who had not undergone BS and 2) the impact of maternal diet on the breast-milk composition. We hypothesized that the milk of women who had undergone BS would be less energy dense and have a lower vitamin A concentration than that of other women. Methods: A multicenter prospective substudy was conducted at 2 university hospitals. Breast-milk samples were collected from 24 normal-weight [NW; mean ± SD body mass index (BMI; kg/m2): 21.5 ± 1.7; mean ± SD age: 29 ± 6 y], 39 overweight (OW; BMI: 26.9 ± 1.5; aged 29 ± 5 y), and 12 obese women (BMI: 35.0 ± 5.7; aged 29 ± 5 y) as well as from 11 women who had undergone BS (BMI: 28.0 ± 4.4; aged 30 ± 4 y) from day 3 until week 6 of lactation. Milk energy and macronutrients (Human Milk Analyzer; Miris) and vitamin A concentrations (iCheck Fluoro; BioAnalyt) were determined at the end of each week. Maternal diet (food-frequency questionnaire) and physical activity (Kaiser Physical Activity Survey) were measured during the third trimester of pregnancy and on day 3 or 4 and during week 6 of lactation. Statistical analyses include 1-factor ANOVA, Spearman and Pearson correlations, and multiple linear regression. Results: In all women, a weekly increase in milk energy, total fat, and total carbohydrates was seen, whereas a weekly decrease in proteins and vitamin A was found during the first 2 wk of lactation, followed by a stable concentration of all nutrients. At week 4, milk protein concentrations were higher in women who had undergone BS (14 g/L) compared with NW (8 g/L; P = 0.005) and OW (9 g/L; P = 0.019) women. At week 5, milk carbohydrate concentrations were higher in women who had undergone BS (74 g/L) compared with NW women (68 g/L; P = 0.042). Conclusions: Breast milk of women who have undergone BS appears to be adequate in energy, macronutrients, and vitamin A during the first 6 wk of lactation. This supports the conclusion that breast feeding should not be discouraged in this group of women. This trial was registered at http://www.clinicaltrials.gov as NCT02515214.

Association of Adipose Tissue Inflammation With Histologic Severity of Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased with the obesity pandemic. We analyzed the transcriptional profiles of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), and phenotypes and functional characteristics of adipocyte tissue macrophages (ATMs), in obese patients undergoing bariatric surgery. METHODS: We collected anthropometric data; plasma samples; and SAT, VAT, and liver tissues from 113 obese patients undergoing bariatric surgery at academic hospitals in Europe (Antwerp and Leuven) and South Africa. Based on clinical and histologic features, patients were assigned to the following groups: obese, NAFLD, nonalcoholic steatohepatitis (NASH), or NASH with fibrosis. Microarray analyses were performed to identify genes expressed differentially among groups. We measured levels of cytokines and chemokines in plasma samples and levels of RNAs in adipose tissues by quantitative reverse-transcription polymerase chain reaction. ATMs were isolated from patients and 13 lean individuals undergoing cholecystectomy (controls), analyzed by flow cytometry, and cultured; immunophenotypes and levels of cytokines and chemokines in supernatants were determined. RESULTS: We observed increased expression of genes that regulate inflammation in adipose tissues from patients with NAFLD and NASH; expression of these genes increased as disease progressed from NAFLD to NASH. We found 111 genes associated with inflammation that were expressed differentially between VAT and SAT. Serum levels of interleukin 8, chemokine (C-C motif) ligand 3, and tumor necrosis factor-α correlated with liver inflammation and NAFLD activity score. We developed 2 models that could be used to determine patients' liver histology based on gene expression in VAT and SAT. Flow cytometry showed increased proportions of CD11c+CD206+ and CCR2+ macrophages in VAT from patients with NASH, and supernatants of cultured macrophages had increased levels of cytokines and chemokines compared with controls. CONCLUSIONS: VAT and SAT from patients with NAFLD and NASH have an increased expression of genes that regulate inflammation, and ATM produce increased levels of inflammatory cytokines, compared with adipose tissues from controls. We identified an expression profile of 5 genes in SAT that accurately predict liver histology in these patients. Transcript profiling: accession numbers: GSE58979 and GSE59045.

Drug disposition before and after gastric bypass: fenofibrate and posaconazole.

AIMS: Roux-en-Y gastric bypass (RYGB) alters the anatomical structure of the gastrointestinal tract, which can result in alterations in drug disposition. The aim of the present study was to evaluate the oral disposition of two compounds belonging to the Biopharmaceutical Classification System Class II - fenofibrate (bile salt-dependent solubility) and posaconazole (gastric pH-dependent dissolution) - before and after RYGB in the same individuals. METHODS: A single-dose pharmacokinetic study with two model compounds - namely, 67 mg fenofibrate (Lipanthyl®) and 400 mg posaconazole (Noxafil®) - was performed in 12 volunteers pre- and post-RYGB. After oral administration, blood samples were collected at different time points up to 48 h after administration. Plasma concentrations were determined by high-performance liquid chromatography in order to calculate the area under the concentration-time curve up to 48 h (AUC0-48 h ), the peak plasma concentration (Cmax) and the time to reach peak concentration (Tmax ). RESULTS: After administration of fenofibrate, no relevant differences in AUC0-48 h , Cmax and Tmax between the pre- and postoperative setting were observed. The geometric mean of the ratio of AUC0-48 h post/pre-RYGB for fenofibrate was 1.10 [95% confidence interval (CI) 0.87, 1.40; P = 0.40]. For posaconazole, an important decrease in AUC0-48 h and Cmax following RYGB was shown; the geometric mean of the AUC0-48 h post/pre-RYGB ratio was 0.68 (95% CI 0.48, 0.96; P = 0.03) and the geometric mean of the Cmax pre/post-RYGB ratio was 0.60 (95% CI 0.39, 0.94; P = 0.03). The decreased exposure of posaconazole could be explained by the increased gastric pH and accelerated gastric emptying of fluids post-RYGB. No difference for Tmax was observed. CONCLUSIONS: The disposition of fenofibrate was not altered after RYGB, whereas the oral disposition of posaconazole was significantly decreased following RYGB.

AURORA: bariatric surgery registration in women of reproductive age - a multicenter prospective cohort study.

BACKGROUND: The expansion of the obesity epidemic is accompanied with an increase in bariatric procedures, in particular in women of reproductive age. The weight loss induced by the surgery is believed to reverse the negative impact of overweight and obesity on female reproduction, however, research is limited to in particular retrospective cohort studies and a growing number of small case-series and case-(control) studies. METHODS/DESIGN: AURORA is a multicenter prospective cohort study. The main objective is to collect long-term data on reproductive outcomes before and after bariatric surgery and in a subsequent pregnancy. Women aged 18-45 years are invited to participate at 4 possible inclusion moments: 1) before surgery, 2) after surgery, 3) before 15 weeks of pregnancy and 4) in the immediate postpartum period (day 3-4). Depending on the time of inclusion, data are collected before surgery (T1), 3 weeks and 3, 6, 12 or x months after surgery (T2-T5) and during the first, second and third trimester of pregnancy (T6-T8), at delivery (T9) and 6 weeks and 6 months after delivery (T10-T11). Online questionnaires are send on the different measuring moments. Data are collected on contraception, menstrual cycle, sexuality, intention of becoming pregnant, diet, physical activity, lifestyle, psycho-social characteristics and dietary supplement intake. Fasting blood samples determine levels of vitamin A, D, E, K, B-1, B-12 and folate, albumin, total protein, coagulation parameters, magnesium, calcium, zinc and glucose. Participants are weighted every measuring moment. Fetal ultrasounds and pregnancy course and complications are reported every trimester of pregnancy. Breastfeeding is recorded and breast milk composition in the postpartum period is studied. DISCUSSION: AURORA is a multicenter prospective cohort study extensively monitoring women before undergoing bariatric surgery until a subsequent pregnancy and postpartum period. TRIAL REGISTRATION: Retrospectively registered (July 2015 - NCT02515214 ).

Roux-en-y gastric bypass attenuates hepatic mitochondrial dysfunction in mice with non-alcoholic steatohepatitis.

OBJECTIVE: No therapy for non-alcoholic steatohepatitis (NASH) has been approved so far. Roux-en-y gastric bypass (RYGB) is emerging as a therapeutic option, although its effect on NASH and related hepatic molecular pathways is unclear from human studies. We studied the effect of RYGB on pre-existent NASH and hepatic mitochondrial dysfunction-a key player in NASH pathogenesis-in a novel diet-induced mouse model nicely mimicking human disease. DESIGN: C57BL/6J mice were fed a high-fat high-sucrose diet (HF-HSD). RESULTS: HF-HSD led to early obesity, insulin resistance and hypercholesterolaemia. HF-HSD consistently induced NASH (steatosis, hepatocyte ballooning and inflammation) with fibrosis already after 12-week feeding. NASH was accompanied by hepatic mitochondrial dysfunction, characterised by decreased mitochondrial respiratory chain (MRC) complex I and IV activity, ATP depletion, ultrastructural abnormalities, together with higher 4-hydroxynonenal (HNE) levels, increased uncoupling protein 2 (UCP2) and tumour necrosis factor-α (TNF-α) mRNA and free cholesterol accumulation. In our model of NASH and acquired mitochondrial dysfunction, RYGB induced sustained weight loss, improved insulin resistance and inhibited progression of NASH, with a marked reversal of fibrosis. In parallel, RYGB preserved hepatic MRC complex I activity, restored ATP levels, limited HNE production and decreased TNF-α mRNA. CONCLUSIONS: Progression of NASH and NASH-related hepatic mitochondrial dysfunction can be prevented by RYGB. RYGB preserves respiratory chain complex activity, thereby restoring energy output, probably by limiting the amount of oxidative stress and TNF-α. These data suggest that modulation of hepatic mitochondrial function contributes to the favourable effect of RYBG on established NASH.

Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations.

AIMS: The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB. METHODS: A single-dose pharmacokinetic study of metoprolol tartrate 200 mg immediate release and controlled release was performed in 14 volunteers before and 6-8 months after RYGB. The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB. RESULTS: After administration of metoprolol immediate and controlled release, no statistically significant difference in the observed area under the curve (AUC(0-24 h)) was shown, although a tendency towards an increased oral exposure could be observed as the AUC(0-24 h) was 32.4% [95% confidence interval (CI) 1.36, 63.5] and 55.9% (95% CI 5.73, 106) higher following RYGB for the immediate and controlled-release formulation, respectively. This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract. The PBPK values predicted by modelling and simulation were similar to the observed data, confirming its validity. CONCLUSIONS: The disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB; there was a tendency to an increase, which was also predicted by PBPK modelling and simulation.

Gestational Weight Gain Following Metabolic Bariatric Surgery: A Scoping Review.

Metabolic bariatric surgery remains the most effective and durable treatment for severe obesity. Women of reproductive age represent the largest demographic group undergoing these procedures. Metabolic bariatric surgery can have both beneficial and adverse effects on pregnancy outcomes. One of the most common adverse effects is fetal growth restriction. To mitigate these adverse effects, it is crucial to explore lifestyle modifications aimed at promoting a healthy pregnancy. Modifiable factors during pregnancy after metabolic bariatric surgery include the amount of gestational weight gain. The aim of this comprehensive review is to provide an overview of what is known about gestational weight gain in pregnancy after bariatric metabolic surgery. This review is focused on the two most performed procedures: sleeve gastrectomy and Roux-en-Y gastric bypass.

Healthcare professionals perceptions of obesity management: An IMI2 SOPHIA qualitative study.

Understanding healthcare professionals' perceptions and approaches to obesity management is limited, as are the barriers impeding effective care. A questionnaire was developed to explore the perception, and barriers to obesity management. To ensure content validity, an expert and stakeholder panel evaluated the relevance and comprehension of each item. Consequently, a cross-sectional survey was administered to endocrinologists (Endo), general practitioners (GP), and pharmacists (Pharm). A 46-item questionnaire was developed, validated, and completed by 502 healthcare professionals (Endo: n = 127; GP: n = 138; Pharm: n = 237). The majority agreed that obesity is a chronic disease (Endo = 96%; GP = 92.7%; Pharm = 87%). The conversation about obesity management is mostly initiated by the healthcare professional (Endo = 95.3%; GP = 73.9%; Pharm = 5.9%) instead of the patient (Endo = 55.1%; GP = 21.7%; Pharm = 11.8%). All professionals stated unanimously that there is a need to optimise obesity care in Belgium with identified barriers: motivational (Endo = 90.8%; GP = 90.8%; Pharm = 89.2%), financial (Endo = 96.9%; GP = 88.5%; Pharm = 76.3%), and a lack of structure (Endo = 81.5%; GP = 78.6%; Pharm = 81.5%). A total of 42.4% of the healthcare providers indicated that they did not follow any additional training. These findings highlight that healthcare professionals recognise obesity as a chronic disease, but that barriers need to be addressed to enhance effective care and support for people living with obesity.

Bitter-tasting drugs tune GDF15 and GLP-1 expression via bitter taste or motilin receptors in the intestine of patients with obesity.

OBJECTIVE: Growth differentiation factor 15 (GDF15), a stress related cytokine, was recently identified as a novel satiety signal acting via the GFRAL receptor located in the hindbrain. Bitter compounds are known to induce satiety via the release of glucagon-like peptide 1 (GLP-1) through activation of bitter taste receptors (TAS2Rs, 25 subtypes) on enteroendocrine cells in the gut. This study aimed to investigate whether and how bitter compounds induce a stress response in intestinal epithelial cells to affect GDF15 expression in patients with obesity, thereby facilitating satiety signaling from the gut. METHODS: The acute effect of oral intake of the bitter-containing medication Plaquenil (hydroxychloroquine sulfate) on plasma GDF15 levels was evaluated in a placebo-controlled, double-blind, randomized, two-visit crossover study in healthy volunteers. Primary crypts isolated from the jejunal mucosa from patients with obesity were stimulated with vehicle or bitter compounds, and the effect on GDF15 expression was evaluated using RT-qPCR or ELISA. Immunofluorescence colocalization studies were performed between GDF15, epithelial cell type markers and TAS2Rs. The role of TAS2Rs was tested by 1) pretreatment with a TAS2R antagonist, GIV3727; 2) determining TAS2R4/43 polymorphisms that affect taste sensitivity to TAS2R4/43 agonists. RESULTS: Acute intake of hydroxychloroquine sulfate increased GDF15 plasma levels, which correlated with reduced hunger scores and plasma ghrelin levels in healthy volunteers. This effect was mimicked in primary jejunal cultures from patients with obesity. GDF15 was expressed in enteroendocrine and goblet cells with higher expression levels in patients with obesity. Various bitter-tasting compounds (medicinal, plant extracts, bacterial) either increased or decreased GDF15 expression, with some also affecting GLP-1. The effect was mediated by specific intestinal TAS2R subtypes and the unfolded protein response pathway. The bitter-induced effect on GDF15/GLP-1 expression was influenced by the existence of TAS2R4 amino acid polymorphisms and TAS2R43 deletion polymorphisms that may predict patient's therapeutic responsiveness. However, the effect of the bitter-tasting antibiotic azithromycin on GDF15 release was mediated via the motilin receptor, possibly explaining some of its aversive side effects. CONCLUSIONS: Bitter chemosensory and pharmacological receptors regulate the release of GDF15 from human gut epithelial cells and represent potential targets for modulating metabolic disorders or cachexia.

Comparative impact of Roux-en-Y gastric bypass, sleeve gastrectomy or diet alone on beta-cell function in insulin-treated type 2 diabetes patients.

Although bariatric surgery is an effective treatment for type 2 diabetes by inducing weight loss and augmenting gut hormone secretion, the immediate effect on beta-cell function itself remains to be elucidated in type 2 diabetes. Therefore, a prospective, randomized trial was performed in 30 patients with insulin-treated type 2 diabetes and a body mass index ≥ 35 kg/m2. Patients were randomly assigned (1:1:1) to Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) in combination with protein-sparing modified fast (PSMF), or to PSMF alone. Eu- and hyperglycemic clamps were performed before and 3 weeks after surgery and/or PSMF initiation. The primary outcome was the evolution of insulin sensitivity and beta-cell function after surgery, calculated using the composite measures of glucose disposal rate, insulin secretion rate, and disposition index (DI). Results revealed that markers of insulin sensitivity increased similarly in all arms (p = 0.43). A higher marker for maximal beta-cell function was observed when comparing SG to PSMF (p = 0.007). The DI showed a clear positive evolution after RYGB and SG, but not after PSMF alone. Altogether, these findings indicate that bariatric surgery results in an immediate beta-cell function recovery in insulin-treated type 2 diabetes.

Urinary phenotyping indicates weight loss-independent metabolic effects of Roux-en-Y gastric bypass in mice.

Patients with a body mass index (BMI) above 35 kg/m(2) with metabolic diseases benefit from Roux-en-Y gastric bypass (RYGB) independently of their final BMI and the amount of body weight lost. However, the weight loss independent metabolic effects induced by RYGB remain less well understood. To elucidate metabolic changes after RYGB, (1)H NMR spectroscopy-based urine metabolic profiles from RYGB (n = 7), ad libitum-fed sham (AL, n = 5), and body-weight-matched sham (BWM, n = 5) operated mice were obtained. Gut morphometry and fecal energy content were analyzed. Food intake and body weight of RYGB mice were significantly reduced (p = 0.001) compared to sham-AL. There was a strong tendency that BWM-shams required less food to maintain the same body weight as RYGB mice (p = 0.05). No differences were found in fecal energy content between the groups, excluding malabsorption in RYGB animals. Unlike RYGB-operated rats, gut hypertrophy was not observed in RYGB-operated mice. Urinary tricarboxylic acid cycle intermediates were higher in the sham groups, suggesting altered mitochondrial metabolism after RYGB surgery. Higher urinary levels of trimethylamine, hippurate and trigonelline in RYGB mice indicate that the RYGB operation caused microbial disturbance. Taken together, we demonstrate for the first time that there are RYGB specific metabolic effects, which are independent of food intake and body weight loss. Increased utilization of TCA cycle intermediates and altered gut microbial-host co-metabolites might indicate increased energy expenditure and microbial changes in the gut, respectively.

Personalized remotely guided preventive exercise therapy for a healthy heart (PRIORITY): protocol for an assessor-blinded, multicenter randomized controlled trial.

Aims: A key treatment for patients with varying stages of heart failure with preserved ejection fraction (HFpEF) is exercise. Yet, despite a Class 1A recommendation, only one-third of patients exercise sufficiently. A huge treatment gap exists between guidelines and clinical practice. PRIORITY aims to establish the feasibility, clinical effectiveness and cost-effectiveness of a hybrid centre and home-based personalized exercise and physical activity intervention for patients along the HFpEF continuum. Methods: An assessor-blinded, multicenter randomized controlled trial will be conducted among 312 patients along the HFpEF continuum. Participants will be randomized (1:1) to the PRIORITY intervention or a comparator group receiving only a written exercise prescription. Participants in the PRIORITY group will receive 18 supervised centre-based exercise sessions during one year, supplemented with a remotely guided home-based physical activity program. Outcomes will be assessed at baseline, 4 months, one and two years. The primary outcome is the peak oxygen uptake (pVO2) at 1-year. Secondary outcomes include physical activity, other physical fitness parameters, cardiovascular health, echocardiographic parameters, health-related quality of life and costs at 1-year FU. Machine learning algorithms will analyse big data on physical activity collected during the 1-year intervention to develop models that can predict physical activity uptake and adherence as well as changes in fitness and health. A cost-utility analysis will be performed to evaluate the cost-effectiveness of the PRIORITY intervention compared to the control condition. Discussion: We anticipate that participants in the supervised home-based exercise intervention group will have a greater increase in pVO2 compared to those receiving a written exercise prescription. Trial registration number: This trial is registered at ClinicalTrials.gov (NCT04745013) and is currently in the recruitment stage.

Effect of sleeve gastrectomy and Roux-en-Y gastric bypass on gastrointestinal physiology.

BACKGROUND: Knowledge regarding the gastrointestinal physiology after sleeve gastrectomy and Roux-en-Y gastric bypass is urgently needed to understand, prevent and treat the nutritional and pharmacological complications of bariatric surgery. AIM: To investigate the effect of sleeve gastrectomy and Roux-en-Y gastric bypass on gastrointestinal motility (e.g., transit and pressure), pH, and intestinal bile acid concentration. MATERIAL AND METHODS: An exploratory cross-sectional study was performed in six participants living with obesity, six participants who underwent sleeve gastrectomy, and six participants who underwent Roux-en-Y gastric bypass. During the first visit, a wireless motility capsule (SmartPill©) was ingested after an overnight fast to measure gastrointestinal transit, pH, and pressure. During the second visit, a gastric emptying scintigraphy test of a nutritional drink labeled with 99mTc-colloid by a dual-head SPECT gamma camera was performed to measure gastric emptying half-time (GET1/2). During the third visit, two customized multiple lumen aspiration catheters were positioned to collect fasting and postprandial intestinal fluids to measure bile acid concentration. RESULTS: Immediate pouch emptying (P = 0.0007) and a trend for faster GET1/2 (P = 0.09) were observed in both bariatric groups. There was a tendency for a shorter orocecal transit in participants with sleeve gastrectomy and Roux-en-Y gastric bypass (P = 0.08). The orocecal segment was characterized by a higher 25th percentile pH (P = 0.004) and a trend for a higher median pH in both bariatric groups (P = 0.07). Fasting total bile acid concentration was 7.5-fold higher in the common limb after Roux-en-Y gastric bypass (P < 0.0001) and 3.5-fold higher in the jejunum after sleeve gastrectomy (P = 0.009) compared to obesity. Postprandial bile acid concentration was 3-fold higher in the jejunum after sleeve gastrectomy (P = 0.0004) and 6.5-fold higher in the common limb after Roux-en-Y gastric bypass (P < 0.0001) compared to obesity. CONCLUSION: The anatomical alterations of sleeve gastrectomy and Roux-en-Y gastric bypass have an important impact on gastrointestinal physiology. This data confirms changes in transit and pH and provides the first evidence for altered intraluminal bile acid concentration.

Patients with a History of Bariatric Surgery Are 8 Years Younger at Presentation with Severe Alcoholic Hepatitis.

PURPOSE: Patients with prior bariatric surgery (BS) are at risk to develop alcohol use disorder (AUD) and alcohol-related liver disease (ALD). Severe alcoholic hepatitis (sAH) is one of the most severe manifestations of ALD with a 28-day mortality of 20-50%. The impact of prior BS on patients presenting with sAH was assessed. METHODS: From 01/2008 to 04/2021, consecutive patients admitted to a tertiary referral center with biopsy-proven sAH were included in a database. RESULTS: One hundred fifty-eight sAH patients of which 28 patients had a history of BS (BS group) were identified. Of this BS group, 24 patients underwent a Roux-en-Y gastric bypass (RYGB), 3 a biliopancreatic diversion, 1 an adjustable gastric band, and no patients a sleeve gastrectomy. The proportion of patients with BS increased threefold over time during the study period. Patients in the BS group were significantly younger at diagnosis of sAH (44.3 years vs 52.4 years), were more frequently female, and had a higher body mass index and a higher grade of steatosis on liver biopsy. The correlation between BS and a younger age at diagnosis remained significant in a multivariate regression analysis. There were no differences in disease severity between both groups. Furthermore, there were no differences in corticosteroid response, 28-day, 90-day, or 1-year survival. CONCLUSION: Prior BS is independently associated with a younger age of presentation with sAH, but is not independently associated with a different disease severity or outcome. These findings support the need for early detection of AUD in patients who underwent BS, in particular RYGB.