Medication and supplement pharmacokinetic changes following bariatric surgery: A systematic review and meta-analysis.

OBJECTIVES: To evaluate the impact of bariatric surgery on the pharmacokinetic (PK) parameters of orally administered medications and supplements. METHODS: Systematic searches of bibliographic databases were conducted to identify studies. Pooled effect estimates from different surgical procedures were calculated using a random-effects model. RESULTS: Quantitative data were synthesized from 58 studies including a total of 1985 participants. Whilst 40 medications and 6 supplements were evaluated across these studies, heterogeneity and missing information reduced the scope of the meta-analysis to the following medications and supplements: atorvastatin, paracetamol, omeprazole, midazolam, vitamin D, calcium, zinc, and iron supplements. There were no significant differences in PK parameters post-surgery for the drugs atorvastatin and omeprazole, and supplements calcium, ferritin, and zinc supplements. Paracetamol showed reduced clearance (mean difference [MD] = -15.56 L/hr, p = 0.0002, I2 = 67%), increased maximal concentration (MD = 6.90 µg/ml, p = 0.006, I2 = 92%) and increased terminal elimination half-life (MD = 0.49 hr, p < 0.0001, I2 = 3%) post-surgery. The remaining 36 medications and 2 supplements were included in a systematic review. Overall, 18 of the 53 drugs and supplements showed post-operative changes in PK parameters. CONCLUSION: This study demonstrates heterogeneity in practice and could not reach conclusive findings for most PK parameters. Prospective studies are needed to inform best practice and enhance patient healthcare and safety following bariatric surgery.

Micronutrient status 2 years after bariatric surgery: a prospective nutritional assessment.

Background: Among commonly performed bariatric surgeries, biliopancreatic diversion with duodenal switch (BPD-DS) provides greater weight loss than Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG), with sustained metabolic improvements. However, the risk of long-term nutritional deficiencies due to the hypoabsorptive component of BPD-DS hinders its widespread use. Objective: The aim of the study was to examine nutritional status over 2 years after BPD-DS, RYGB or SG. Methods: Patients were recruited in the REMISSION trial (NCT02390973), a single-center, prospective study. Out of 215 patients, 73, 48 and 94, respectively, underwent BPD-DS, RYGB or SG. Weight loss, micronutrient serum levels (including iron, calcium, parathormone, vitamins A, B12 and D), and nutritional supplementation were assessed over 2 years. Patients were supplemented according to the type of surgery and individual micronutrient level evolution. Results: At baseline, BPD-DS patients were younger than SG patients (p = 0.0051) and RYGB patients had lower body mass index (p < 0.001). Groups had similar micronutrient levels before surgery, with vitamin D insufficiency as the most prevalent nutritional problem (SG: 38.3%, RYGB: 39.9%, BPD-DS: 54.8%, p = 0.08). BPD-DS patients showed lower levels of iron, calcium and vitamin A than SG patients at 24 months. Groups had similar levels of vitamin D at 24 months. Prevalence of vitamin D, calcium, iron, vitamin A and vitamin B12 deficiency was similar among groups at 24 months. Rates of vitamin D insufficiency and iron deficiency were lower at 24 months than at baseline. Micronutrient intake was consistent with recommendations in groups post-surgery, but most BPD-DS patients took vitamin A and vitamin D supplement doses above initial recommendations. Conclusion: With appropriate medical and nutritional management, all surgeries led to similar rates of vitamin D, calcium, iron, vitamin A and vitamin B12 deficiencies at 24 months. However, initial vitamin A and vitamin D supplementation recommendations for BPD-DS patients should be revised upwards.

Resistance training and cardiometabolic risk in women with metabolically healthy and unhealthy obesity.

Despite some reported benefits, there is a low quality of evidence for resistance training (RT) improving metabolic health of individuals with overweight or obesity. We evaluated the impact of RT on body composition, cardiorespiratory fitness (CRF) and physical performance, lipid-lipoprotein profile, inflammation, and glucose-insulin homeostasis in 51 postmenopausal women versus 29 controls matched for age, obesity, and physical activity. Exercised women were further subdivided for comparison of RT effects into those presenting metabolically healthy obesity (MHO) and those with metabolically unhealthy obesity (MUHO) classified according to Karelis and Rabasa-Lhoret or an approach based on adipose tissue secretory dysfunction using the plasma adiponectin(A)/leptin (L) ratio. Participants followed a 4-month weekly RT program targeting major muscle groups (3 × 10 repetitions at 80% one repetition maximum (1-RM)). Percent fat marginally decreased and lean body mass increased (0.01 < p < 0.05) while CRF and muscular strength improved in all women, after RT (effect size (ES): 0.11-1.21 (trivial to large effects), p ˂ 0.01). Fasting plasma triacylglycerol and high-density lipoprotein-cholesterol levels slightly increased and decreased, respectively, in participants with MHO using the A/L ratio approach (ES: -0.47 to 1.07 (small to large effects), p ˂ 0.05). Circulating interleukin-6 soluble receptor decreased in both groups and soluble tumor necrosis factor receptor-1/soluble tumor necrosis factor receptor-2 in women with MUHO only, irrespective of definition (ES: -0.42 to -0.84 (small to large effects), p ˂ 0.05). Glucose-insulin homeostasis was unchanged regardless of group or definition. RT improved physical performance and body composition but had a lesser impact on cardiometabolic risk in women with obesity, irrespective of their metabolic phenotype.

Acceptability and Feasibility of the Telehealth Bariatric Behavioral Intervention to Increase Physical Activity Before Bariatric Surgery: A Single-Case Experimental Study (Part I).

BACKGROUND: Physical activity (PA) can play an important role in optimizing metabolic/bariatric surgery (MBS) outcomes. However, many MBS patients have difficulty increasing PA, necessitating the development of theory-driven counseling interventions. This study aimed to (1) assess the feasibility and acceptability of the TELEhealth BARIatric behavioral intervention (TELE-BariACTIV) trial protocol/methods and intervention, which was designed to increase moderate-to-vigorous intensity physical activity (MVPA) in adults awaiting MBS and (2) estimate the effect of the intervention on MVPA. METHODS: This trial used a repeated single-case experimental design. Twelve insufficiently active adults awaiting MBS received 6 weekly 45-min PA videoconferencing counseling sessions. Feasibility and acceptability data (i.e., refusal, recruitment, retention, attendance, and attrition rates) were tracked and collected via online surveys, and interviews. MVPA was assessed via accelerometry pre-, during, and post-intervention. RESULTS: Among the 24 patients referred to the research team; five declined to participate (refusal rate = 20.8%) and seven were ineligible or unreachable. The recruitment rate was 1.2 participants per month between 2021-09 and 2022-07. One participant withdrew during the baseline phase, and one after the intervention (retention rate = 83.3%). No participant dropouts occurred during the intervention and 98.6% of sessions were completed. Participants' anticipated and retrospective acceptability of the intervention was 3.2/4 (IQR, 0.5) and 3.0/4 (IQR, 0.2), respectively. There was a statistically significant increase in MVPA [Tau-U = 0.32(0.11; 0.51)] from pre- to post-intervention. CONCLUSION: Despite a low recruitment rate, which could be explained by circumstances (COVID-19 pandemic), results support feasibility, acceptability, and preliminary efficacy of the TELE-Bari-ACTIV intervention for increasing MVPA in patients awaiting MBS.

Attitudes and Behaviors towards Food and Weight in Late Pregnancy: A Comparative Approach between Individuals with and without Previous Bariatric Surgery.

The aims of this study were to compare, between pregnant individuals with and without bariatric surgery: (1) eating behaviors, (2) intuitive eating components and, (3) attitudes towards weight gain. This retrospective study included data collected in healthy pregnant individuals with and without previous bariatric surgery who were recruited at the Centre Hospitalier Universitaire (CHU) de Québec-Université Laval. Pregnant individuals who underwent bariatric surgery (biliopancreatic bypass with duodenal switch [n = 14] or sleeve gastrectomy [n = 5]) were individually matched, for age (±0.4 years) and body mass index (BMI) (±0.3 kg/m2), with pregnant individuals who have not received bariatric surgery. In the second trimester, participants completed the Three Factor Eating Questionnaire (TFEQ) and the Intuitive Eating Scale 2 (IES-2). In the third trimester, participants completed the French version of the Pregnancy Weight Gain Attitude Scale assessing attitudes towards weight gain. Pregnant individuals who have had bariatric surgery had a higher score for flexible restraint and a lower score for situational susceptibility to disinhibition compared to individuals who have not had undergone bariatric surgery (2.89 ± 1.15 vs. 1.95 ± 1.31; p = 0.04 and 1.11 ± 1.29 vs. 2.79 ± 1.44, respectively; p < 0.001). Regarding intuitive eating, pregnant individuals who experienced bariatric surgery had a higher score for reliance on internal hunger and satiety cues and a lower one for unconditional permission to eat compared with those who had not experienced bariatric surgery (3.99 ± 0.81 vs. 3.30 ± 1.03; p = 0.02 and 3.28 ± 0.54 vs. 3.61 ± 0.68, respectively; p = 0.03). No difference in attitudes towards weight gain was observed between groups. Overall, pregnant individuals who had undergone bariatric surgery had different eating behaviors and intuitive eating components compared to pregnant individuals without bariatric surgery. These results need to be confirmed in further studies with larger sample sizes.

Preoperative predictors of type 2 diabetes remission after bilio-pancreatic diversion with duodenal switch.

BACKGROUND: Many patients achieve short-term type 2 diabetes (T2D) remission after bariatric surgery, but relapses are common. Diabetes outcomes after bariatric surgery vary across procedures and populations. T2D remission scores are simple clinical tools developed to predict remission after bariatric surgery. However, they have never been tested after Biliopancreatic diversion with duodenal switch (BPD-DS). OBJECTIVES: The aim of this study was to compare the predictive value of T2D remission scores and preoperative diabetes characteristics in predicting T2D remission after BPD-DS. SETTING: Quebec Heart and Lung Institute - Laval University. METHODS: We retrospectively identified 918 patients with preoperative T2D who had undergone BPD-DS. Retrospective chart review was performed and variables used to calculate predictive scores were captured. T2D status was assessed annually for up to 10 years postop. Predictive values for each score (DiarRem, Ad Diarem, and Diabetter) and single preoperative diabetes characteristics used to construct these algorithms were evaluated by area under receiver operating characteristic curves (AUC). RESULTS: Diabetter showed greater performance for prediction of durable diabetes remission than other algorithms with acceptable discriminative ability (AUC between .69 and .79), but was not superior to T2D duration as a single predictor (P = .24 and P = .18). At 10 years, T2D duration had a better discriminative ability for the prediction of T2D remission than all 3 predictive models (AUC = .85, P < .05). CONCLUSIONS: Better chances for T2D remission following BPD-DS are associated with a shorter duration or T2D before surgery. Duration of T2D alone offers an excellent predictive ability and is a convenient alternative to diabetes remission scores to estimate chances of long-term diabetes remission after BPD-DS.

Factors Associated with Excess Skin After Bariatric Surgery: a Mixed-Method Study.

PURPOSE: After metabolic and bariatric surgery (MBS), many patients have excess skin (ES), which can cause inconveniences. Identifying factors related to ES quantity and inconveniences is crucial to inform interventions. The aim of this study was to identify sociodemographic, physical, psychosocial, and behavioral factors associated with ES quantity and inconveniences. MATERIALS AND METHODS: A mixed-method study with a sequential explanatory design was conducted with 124 adults (92% women, Mage 46.5 ± 9.9 years, Mtime post-MBS 34.2 ± 27.6 months). During phase I, ES quantity (arms, abdomen, thighs) and inconveniences and sociodemographic, anthropometric, clinical, and behavioral outcomes were assessed. In phase II, 7 focus groups were performed with 37 participants from phase I. A triangulation protocol was completed to identify convergences, complementarities, and dissonances from quantitative and qualitative data. RESULTS: Quantitative data indicate only ES quantity on arms was associated with ES inconveniences on arms (r = .36, p < .01). Total ES quantity was associated with maximal body mass index (BMI) reached pre-MBS (r = .48, p < .05) and current BMI (r = .35, p < .05). Greater ES inconvenience was associated with higher social physique anxiety and age (R2 = .50, p < .01). Qualitative data were summarized into 4 themes: psychosocial experiences living with ES, physical ailments due to ES, essential support and unmet needs, and beliefs of ES quantity causes. CONCLUSION: Measured ES quantity is related to higher BMI, but not reported inconveniences. Greater self-reported ES quantity and inconveniences were associated with body image concerns.

Prevalence of Helicobacter pylori Infection in Bariatric Surgery Patients.

OBJECTIVE: To determine the rate of histology-proven Helicobacter pylori (HP) infection in patients undergoing bariatric surgery and to identify risk factors for HP infection. METHODS: In a retrospective analysis, patients who underwent bariatric surgery with gastric resection in a single hospital between January 2004 and January 2019 were analyzed. For each patient, a surgical specimen was submitted for anatomopathological examination and analyzed for gastritis or other anomalies. When gastritis was present, HP infection was confirmed by the identification of curvilinear bacilli in conventional histology or by specific immunohistochemical detection of HP antigen. RESULTS: A total of 6388 specimens were available for review (4365 women, 2023 men) with a mean age of 44.9 ± 11.2 years and a mean body mass index (BMI) of 49.3 ± 8.2 kg/m2. Histology-proven HP infection rate was 6.3% (n = 405). There was no significant difference in sex, BMI, and body weight between HP + and HP - patients. Logistic regressions identified age as a risk factor for HP infection in this population (OR 1.02, p < 0.0001, CI 95% 1.01-1.03 for every 1-year increase, OR 1.26, p < 0.0001, CI 95% 1.14-1.40 for every 10-year increase). CONCLUSIONS: The rate of histology-proven HP infection is low in patients with severe obesity who present for bariatric surgery and is associated with age.

Association between Circulating Amino Acids and COVID-19 Severity.

The severity of the symptoms associated with COVID-19 is highly variable, and has been associated with circulating amino acids as a group of analytes in metabolomic studies. However, for each individual amino acid, there are discordant results among studies. The aims of the present study were: (i) to investigate the association between COVID-19-symptom severity and circulating amino-acid concentrations; and (ii) to assess the ability of circulating amino-acid levels to predict adverse outcomes (intensive-care-unit admission or hospital death). We studied a sample of 736 participants from the Biobanque Québécoise COVID-19. All participants tested positive for COVID-19, and the severity of symptoms was determined using the World-Health-Organization criteria. Circulating amino acids were measured by HPLC-MS/MS. We used logistic models to assess the association between circulating amino acids concentrations and the odds of presenting mild vs. severe or mild vs. moderate symptoms, as well as their accuracy in predicting adverse outcomes. Patients with severe COVID-19 symptoms were older on average, and they had a higher prevalence of obesity and type 2 diabetes. Out of 20 amino acids tested, 16 were significantly associated with disease severity, with phenylalanine (positively) and cysteine (inversely) showing the strongest associations. These associations remained significant after adjustment for age, sex and body mass index. Phenylalanine had a fair ability to predict the occurrence of adverse outcomes, similar to traditionally measured laboratory variables. A multivariate model including both circulating amino acids and clinical variables had a 90% accuracy at predicting adverse outcomes in this sample. In conclusion, patients presenting severe COVID-19 symptoms have an altered amino-acid profile, compared to those with mild or moderate symptoms.

Bariatric Surgery Should Be Offered to Active-Duty Military Personnel: a Retrospective Study of the Canadian Armed Forces' Experience.

PURPOSE: Like most Western armies, obesity affects Canadian Armed Forces (CAF) personnel. Bariatric surgery is an effective treatment for obesity. However, this is not yet accepted for active-duty soldiers in most countries. The CAF have approved bariatric surgery since 2005. Our aim is to assess weight loss, resolution of obesity-related comorbidities, and impacts of bariatric surgery on military careers. MATERIALS AND METHODS: We retrospectively reviewed the perioperative data, long-term bariatric results, and military outcomes of 108 CAF active-duty military personnel who underwent bariatric surgery in Canada over a 61-month period. RESULTS: The cohort was predominantly male (66.7%) with a mean preoperative body mass index (BMI) of 43.6 ± 5.8 kg/m2. Roux-Y gastric bypass was performed in 59 patients, sleeve gastrectomy in 29, and gastric banding in 20. All the surgeries were performed laparoscopically. The total body weight loss at the last follow-up visit was 22.5 ± 11.0%. Remission or improvement of hypertension was observed in 91.2%, diabetes in 85.7%, gastroesophageal reflux disorder (GERD) in 43.6%, sleep apnea in 43.1%, and dyslipidemia in 42.9%. One patient (0.9%) was medically released due to postoperative complications. Fifteen patients (13.9%) were deployed postoperatively. The combined deployable and possibly deployable statuses increased from 35.4% preoperatively to 47.9% postoperatively. CONCLUSION: This is the largest series of bariatric surgeries performed in active-duty military personnel. Bariatric surgery is effective and safe and improves deployability without impairing military careers. These results are relevant to the military of many industrialized countries. Bariatric surgery should be considered for all active-duty military personnel who meet surgical criteria for the treatment of obesity.

17ß-hydroxysteroid dehydrogenase type 2 activity, expression and cellular localization in abdominal adipose tissues from women.

CONTEXT: 17ß-hydroxysteroid dehydrogenase type 2 (17ß-HSD2) may be involved in the local modulation of estradiol (E2) availability in adipose tissues. OBJECTIVE: To assess the conversion of E2 into estrone (E1) as well as the expression of 17ß-HSD2 and its localization in omental (OM) and subcutaneous (SC) adipose tissues obtained from women. METHODS: Rates of 14 C-E1 formation from 14 C-E2 were measured in OM and SC adipose tissue homogenates from 29 women. Specific 17ß-HSD2 inhibitor EM-919 was tested in OM and SC adipose tissue homogenates (n = 6). 17ß-HSD2 mRNA expression was measured in whole OM and SC adipose tissues (n = 14). Cellular localization of the enzyme was examined using immunohistochemistry. Anthropometric measurements were obtained and body composition as well as body fat distribution were measured. RESULTS: Significant 14 C-E1 formation from 14 C-E2 in OM and SC tissue homogenates was detected. The rate of 14 C-E1 formation was significantly higher in OM than SC adipose tissue (p < .0001). The conversion of 14 C-E2 to 14 C-E1 was significantly inhibited by EM-919 in OM (p < .05) and SC (p < .05) adipose tissues. Significantly higher expression of 17ß-HSD2 mRNA in OM versus SC fat was found (p = .03). 17ß-HSD2 was localized in the vasculature of OM and SC tissues. Significant negative associations were detected between OM 17ß-HSD2 activity and body mass index, WC, lean body mass as well as SC adipose tissue areas. CONCLUSION: 17ß-HSD2 converts E2 to E1 in OM and SC adipose tissues of women. The activity of this enzyme decreases with increasing adiposity.

Human gut microbiota after bariatric surgery alters intestinal morphology and glucose absorption in mice independently of obesity.

OBJECTIVE: Bariatric surgery is an effective treatment for type 2 diabetes (T2D) that changes gut microbial composition. We determined whether the gut microbiota in humans after restrictive or malabsorptive bariatric surgery was sufficient to lower blood glucose. DESIGN: Women with obesity and T2D had biliopancreatic diversion with duodenal switch (BPD-DS) or laparoscopic sleeve gastrectomy (LSG). Faecal samples from the same patient before and after each surgery were used to colonise rodents, and determinants of blood glucose control were assessed. RESULTS: Glucose tolerance was improved in germ-free mice orally colonised for 7 weeks with human microbiota after either BPD-DS or LSG, whereas food intake, fat mass, insulin resistance, secretion and clearance were unchanged. Mice colonised with microbiota post-BPD-DS had lower villus height/width and crypt depth in the distal jejunum and lower intestinal glucose absorption. Inhibition of sodium-glucose cotransporter (Sglt)1 abrogated microbiota-transmissible improvements in blood glucose control in mice. In specific pathogen-free (SPF) rats, intrajejunal colonisation for 4 weeks with microbiota post-BPD-DS was sufficient to improve blood glucose control, which was negated after intrajejunal Sglt-1 inhibition. Higher Parabacteroides and lower Blautia coincided with improvements in blood glucose control after colonisation with human bacteria post-BPD-DS and LSG. CONCLUSION: Exposure of rodents to human gut microbiota after restrictive or malabsorptive bariatric surgery improves glycaemic control. The gut microbiota after bariatric surgery is a standalone factor that alters upper gut intestinal morphology and lowers Sglt1-mediated intestinal glucose absorption, which improves blood glucose control independently from changes in obesity, insulin or insulin resistance.

Trimester-Specific Serum Fructosamine in Association with Abdominal Adiposity, Insulin Resistance, and Inflammation in Healthy Pregnant Individuals.

This study aimed to (1) characterize the variations in serum fructosamine across trimesters and according to pre-pregnancy BMI (ppBMI), and (2) examine associations between fructosamine and adiposity/metabolic markers (ppBMI, first-trimester adiposity, leptin, glucose homeostasis, and inflammation measurements) during pregnancy. Serum fructosamine, albumin, fasting glucose and insulin, leptin, adiponectin, interleukin-6 (IL-6), and C-reactive protein (CRP) concentrations were measured at each trimester. In the first trimester, subcutaneous (SAT) and visceral (VAT) adipose tissue thicknesses were estimated by ultrasound. In the 101 healthy pregnant individuals included (age: 32.2 ± 3.5 y.o.; ppBMI: 25.5 ± 5.5 kg/m2), fructosamine concentrations decreased during pregnancy whereas albumin-corrected fructosamine concentrations increased (p < 0.0001 for both). Notably, fructosamine concentrations were inversely associated with ppBMI, first-trimester SAT, VAT, and leptin (r = −0.55, r = −0.61, r = −0.48, r = −0.47, respectively; p < 0.0001 for all), first-trimester fasting insulin and HOMA-IR (r = −0.46, r = −0.46; p < 0.0001 for both), and first-trimester IL-6 (r = −0.38, p < 0.01). However, once corrected for albumin, most of the correlations lost strength. Once adjusted for ppBMI, fructosamine concentrations were positively associated with third-trimester fasting glucose and CRP (r = 0.24, r = 0.27; p < 0.05 for both). In conclusion, serum fructosamine is inversely associated with adiposity before and during pregnancy, with markers of glucose homeostasis and inflammation, but the latter associations are partially influenced by albumin concentrations and ppBMI.

Acceptability and Feasibility of the Telehealth Bariatric Behavioral Intervention to Increase Physical Activity: Protocol for a Single-Case Experimental Study.

BACKGROUND: Regular physical activity (PA) is recommended to optimize weight and health outcomes in patients who have undergone metabolic and bariatric surgery (MBS). However, >70% of patients have low PA levels before MBS that persist after MBS. Although behavioral interventions delivered face-to-face have shown promise for increasing PA among patients who have undergone MBS, many may experience barriers, preventing enrollment into and adherence to such interventions. Delivering PA behavior change interventions via telehealth to patients who have undergone MBS may be an effective strategy to increase accessibility and reach, as well as adherence. OBJECTIVE: This paper reports the protocol for a study that aims to assess the feasibility and acceptability of the protocol or methods and the Telehealth Bariatric Behavioral Intervention (TELE-BariACTIV). The intervention is designed to increase moderate-to-vigorous intensity PA (MVPA) in patients awaiting bariatric surgery and is guided by a multitheory approach and a patient perspective. Another objective is to estimate the effect of the TELE-BariACTIV intervention on presurgical MVPA to determine the appropriate sample size for a multicenter trial. METHODS: This study is a multicenter trial using a repeated (ABAB'A) single-case experimental design. The A phases are observational phases without intervention (A1=pre-MBS phase; A2=length personalized according to the MBS date; A3=7 months post-MBS phase). The B phases are interventional phases with PA counseling (B1=6 weekly pre-MBS sessions; B2=3 monthly sessions starting 3 months after MBS). The target sample size is set to 12. Participants are inactive adults awaiting sleeve gastrectomy who have access to a computer with internet and an interface with a camera. The participants are randomly allocated to a 1- or 2-week baseline period (A1). Protocol and intervention feasibility and acceptability (primary outcomes) will be assessed by recording missing data, refusal, recruitment, retention, attendance, and attrition rates, as well as via web-based acceptability questionnaires and semistructured interviews. Data collected via accelerometry (7-14 days) on 8 occasions and via questionnaires on 10 occasions will be analyzed to estimate the effect of the intervention on MVPA. Generalization measures assessing the quality of life, anxiety and depressive symptoms, and theory-based constructs (ie, motivational regulations for PA, self-efficacy to overcome barriers to PA, basic psychological needs satisfaction and frustration, PA enjoyment, and social support for PA; secondary outcomes for a future large-scale trial) will be completed via web-based questionnaires on 6-10 occasions. The institutional review board provided ethics approval for the study in June 2021. RESULTS: Recruitment began in September 2021, and all the participants were enrolled (n=12). Data collection is expected to end in fall 2023, depending on the MBS date of the recruited participants. CONCLUSIONS: The TELE-BariACTIV intervention has the potential for implementation across multiple settings owing to its collaborative construction that can be offered remotely. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39633.

Altered branched-chain α-keto acid metabolism is a feature of NAFLD in individuals with severe obesity.

Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). Here, we aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-keto acids (BCKAs), and hepatic BCKDK expression are associated with the presence and severity of nonalcoholic fatty liver disease (NAFLD). Eighty metabolites (3 BCKAs, 14 amino acids, 43 acylcarnitines, 20 ceramides) were quantified in plasma from 288 patients with bariatric surgery with severe obesity and scored liver biopsy samples. Metabolite principal component analysis factors, BCKAs, branched-chain amino acids (BCAAs), and the BCKA/BCAA ratio were tested for associations with steatosis grade and presence of nonalcoholic steatohepatitis (NASH). Of all analytes tested, only the Val-derived BCKA, α-keto-isovalerate, and the BCKA/BCAA ratio were associated with both steatosis grade and NASH. Gene expression analysis in liver samples from 2 independent bariatric surgery cohorts showed that hepatic BCKDK mRNA expression correlates with steatosis, ballooning, and levels of the lipogenic transcription factor SREBP1. Experiments in AML12 hepatocytes showed that SREBP1 inhibition lowered BCKDK mRNA expression. These findings demonstrate that higher plasma levels of BCKA and hepatic expression of BCKDK are features of human NAFLD/NASH and identify SREBP1 as a transcriptional regulator of BCKDK.

Molecular remodeling of adipose tissue is associated with metabolic recovery after weight loss surgery.

BACKGROUND: Bariatric surgery is an effective therapy for individuals with severe obesity to achieve sustainable weight loss and to reduce comorbidities. Examining the molecular signature of subcutaneous adipose tissue (SAT) following different types of bariatric surgery may help in gaining further insight into their distinct metabolic impact. RESULTS: Subjects undergoing biliopancreatic diversion with duodenal switch (BPD-DS) showed a significantly higher percentage of total weight loss than those undergoing gastric bypass or sleeve gastrectomy (RYGB + SG) (41.7 ± 4.6 vs 28.2 ± 6.8%; p = 0.00005). Individuals losing more weight were also significantly more prone to achieve both type 2 diabetes and dyslipidemia remission (OR = 0.75; 95%CI = 0.51-0.91; p = 0.03). Whole transcriptome and methylome profiling showed that bariatric surgery induced a profound molecular remodeling of SAT at 12 months postoperative, mainly through gene down-regulation and hypermethylation. The extent of changes observed was greater following BPD-DS, with 61.1% and 49.8% of up- and down-regulated genes, as well as 85.7% and 70.4% of hyper- and hypomethylated genes being exclusive to this procedure, and mostly associated with a marked decrease of immune and inflammatory responses. Weight loss was strongly associated with genes being simultaneously differentially expressed and methylated in BPD-DS, with the strongest association being observed for GPD1L (r2 = 0.83; p = 1.4 × 10-6). CONCLUSIONS: Present findings point to the greater SAT molecular remodeling following BPD-DS as potentially linked with higher metabolic remission rates. These results will contribute to a better understanding of the metabolic pathways involved in the response to bariatric surgery and will eventually lead to the development of gene targets for the treatment of obesity. Trial registration ClinicalTrials.gov NCT02390973.

Impact of weight loss on brain age: Improved brain health following bariatric surgery.

Individuals living with obesity tend to have increased brain age, reflecting poorer brain health likely due to grey and white matter atrophy related to obesity. However, it is unclear if older brain age associated with obesity can be reversed following weight loss and cardiometabolic health improvement. The aim of this study was to assess the impact of weight loss and cardiometabolic improvement following bariatric surgery on brain health, as measured by change in brain age estimated based on voxel-based morphometry (VBM) measurements. We used three distinct datasets to perform this study: 1) CamCAN dataset to train the brain age prediction model, 2) Human Connectome Project (HCP) dataset to investigate whether individuals with obesity have greater brain age than individuals with normal weight, and 3) pre-surgery, as well as 4, 12, and 24 month post-surgery data from participants (n = 87, age: 44.0 ± 9.2 years, BMI: 43.9 ± 4.2 kg/m2) who underwent a bariatric surgery to investigate whether weight loss and cardiometabolic improvement as a result of bariatric surgery lowers the brain age. As expected, our results from the HCP dataset showed a higher brain age for individuals with obesity compared to individuals with normal weight (T-value = 7.08, p-value < 0.0001). We also found significant improvement in brain health, indicated by a decrease of 2.9 and 5.6 years in adjusted delta age at 12 and 24 months following bariatric surgery compared to baseline (p-value < 0.0005 for both). While the overall effect seemed to be driven by a global change across all brain regions and not from a specific region, our exploratory analysis showed lower delta age in certain brain regions (mainly in somatomotor, visual, and ventral attention networks) at 24 months. This reduced age was also associated with post-surgery improvements in BMI, systolic/diastolic blood pressure, and HOMA-IR (T-valueBMI=4.29, T-valueSBP=4.67, T-valueDBP=4.12, T-valueHOMA-IR=3.16, all p-values < 0.05). In conclusion, these results suggest that obesity-related brain health abnormalities (as measured by delta age) might be reversed by bariatric surgery-induced weight loss and widespread improvements in cardiometabolic alterations.

Mendelian Randomization Analysis Identifies Blood Tyrosine Levels as a Biomarker of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a complex disease associated with premature mortality. Its diagnosis is challenging, and the identification of biomarkers causally influenced by NAFLD may be clinically useful. We aimed at identifying blood metabolites causally impacted by NAFLD using two-sample Mendelian randomization (MR) with validation in a population-based biobank. Our instrument for genetically predicted NAFLD included all independent genetic variants from a recent genome-wide association study. The outcomes included 123 blood metabolites from 24,925 individuals. After correction for multiple testing, a positive effect of NAFLD on plasma tyrosine levels but not on other metabolites was identified. This association was consistent across MR methods and was robust to outliers and pleiotropy. In observational analyses performed in the Estonian Biobank (10,809 individuals including 359 patients with NAFLD), after multivariable adjustment, tyrosine levels were positively associated with the presence of NAFLD (odds ratio per 1 SD increment = 1.23 [95% confidence interval = 1.12-1.36], p = 2.19 × 10-5). In a small proof-of-concept study on bariatric surgery patients, blood tyrosine levels were higher in patients with NAFLD than without. This study revealed a potentially causal effect of NAFLD on blood tyrosine levels, suggesting it may represent a new biomarker of NAFLD.

Increased Adipose Tissue Indices of Androgen Catabolism and Aromatization in Women With Metabolic Dysfunction.

CONTEXT: Body fat distribution is a risk factor for obesity-associated comorbidities, and adipose tissue dysfunction plays a role in this association. In humans, there is a sex difference in body fat distribution, and steroid hormones are known to regulate several cellular processes within adipose tissue. OBJECTIVE: Our aim was to investigate if intra-adipose steroid concentration and expression or activity of steroidogenic enzymes were associated with features of adipose tissue dysfunction in individuals with severe obesity. METHODS: Samples from 40 bariatric candidates (31 women, 9 men) were included in the study. Visceral (VAT) and subcutaneous adipose tissue (SAT) were collected during surgery. Adipose tissue morphology was measured by a combination of histological staining and semi-automated quantification. Following extraction, intra-adipose and plasma steroid concentrations were determined by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Aromatase activity was estimated using product over substrate ratio, while AKR1C2 activity was measured directly by fluorogenic probe. Gene expression was measured by quantitative PCR. RESULTS: VAT aromatase activity was positively associated with VAT adipocyte hypertrophy (P valueadj < 0.01) and negatively with plasma high-density lipoprotein (HDL)-cholesterol (P valueadj < 0.01), while SAT aromatase activity predicted dyslipidemia in women even after adjustment for waist circumference, age, and hormonal contraceptive use. We additionally compared women with high and low visceral adiposity index (VAI) and found that VAT excess is characterized by adipose tissue dysfunction, increased androgen catabolism mirrored by increased AKR1C2 activity, and higher aromatase expression and activity indices. CONCLUSION: In women, increased androgen catabolism or aromatization is associated with visceral adiposity and adipose tissue dysfunction.

Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b.

Inflammation has profound but poorly understood effects on metabolism, especially in the context of obesity and nonalcoholic fatty liver disease (NAFLD). Here, we report that hepatic interferon regulatory factor 3 (IRF3) is a direct transcriptional regulator of glucose homeostasis through induction of Ppp2r1b, a component of serine/threonine phosphatase PP2A, and subsequent suppression of glucose production. Global ablation of IRF3 in mice on a high-fat diet protected against both steatosis and dysglycemia, whereas hepatocyte-specific loss of IRF3 affects only dysglycemia. Integration of the IRF3-dependent transcriptome and cistrome in mouse hepatocytes identifies Ppp2r1b as a direct IRF3 target responsible for mediating its metabolic actions on glucose homeostasis. IRF3-mediated induction of Ppp2r1b amplified PP2A activity, with subsequent dephosphorylation of AMPKα and AKT. Furthermore, suppression of hepatic Irf3 expression with antisense oligonucleotides reversed obesity-induced insulin resistance and restored glucose homeostasis in obese mice. Obese humans with NAFLD displayed enhanced activation of liver IRF3, with reversion after bariatric surgery. Hepatic PPP2R1B expression correlated with HgbA1C and was elevated in obese humans with impaired fasting glucose. We therefore identify the hepatic IRF3-PPP2R1B axis as a causal link between obesity-induced inflammation and dysglycemia and suggest an approach for limiting the metabolic dysfunction accompanying obesity-associated NAFLD.