Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk.

BACKGROUND AND AIMS: RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases. METHODS: RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of ANGPTL3 protein-truncating variants (PTVs) associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank. RESULTS: In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on low-density lipoprotein cholesterol, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels [-0.37 (interquartile range 0.41) mmol/L] had slightly lower apoB levels (-0.06 ± 0.32 g/L) and similar CAD event rates compared with non-carriers (10.2% vs. 10.9% in carriers vs. non-carriers, P = .60). CONCLUSIONS: PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk.

Glutamate and obesity - what is the link?

PURPOSE OF REVIEW: Many studies using metabolomics have tried to unravel the metabolic signature of obesity and understand the pathophysiology of this complex and heterogeneous disease. Circulating levels of the amino acid glutamate have been consistently associated with obesity and more specifically with measurements of abdominal fat accumulation. The purpose of this narrative review is to highlight recent studies documenting this association. RECENT FINDINGS: Circulating glutamate concentrations have been positively correlated with measurements of central fat accumulation such as waist circumference and visceral adipose tissue area. Moreover, elevated glutamate levels have been linked to a higher prevalence of type 2 diabetes, cardiovascular diseases and nonalcoholic fatty liver disease. The association with adiposity is detected in early life, and genetic predisposition does not appear as a major driver. Glutamate levels reflect in vivo synthesis rather than dietary intake. However, interventions generating metabolic improvements such as incretin receptor agonist treatment or dietary improvements may reduce plasma levels of this amino acid. SUMMARY: Recent findings confirm the consistent association between circulating glutamate and abdominal obesity and its cardiometabolic complications. The pathophysiological pathways underlying this phenomenon are still unclear. Furthermore, studies are needed to establish the usefulness of this analyte as a biomarker of abdominal obesity.

Plasma adiponectin/leptin ratio associates with subcutaneous abdominal and omental adipose tissue characteristics in women.

BACKGROUND: A better understanding of adipose tissue (AT) dysfunction, which includes morphological and functional changes such as adipocyte hypertrophy as well as impaired adipogenesis, lipid storage/mobilization, endocrine and inflammatory responses, is needed in the context of obesity. One dimension of AT dysfunction, secretory adiposopathy, often assessed as a low plasma adiponectin (A)/leptin (L) ratio, is commonly observed in obesity. The aim of this study was to examine markers of AT development and metabolism in 67 women of varying age and adiposity (age: 40-62 years; body mass index, BMI: 17-41 kg/m2) according to levels of adiponectinemia, leptinemia or the plasma A/L ratio. METHODS: Body composition, regional AT distribution and circulating adipokines were determined. Lipolysis was measured from glycerol release in subcutaneous abdominal (SCABD) and omental (OME) adipocytes under basal, isoproterenol-, forskolin (FSK)- and dibutyryl-cyclic AMP (DcAMP)-stimulated conditions. Adipogenesis (C/EBP-α/ß/δ, PPAR-γ2 and SREBP-1c) and lipid metabolism (ß2-ARs, HSL, FABP4, LPL and GLUT4) gene expression (RT-qPCR) was assessed in both fat depots. Participants in the upper versus lower tertile of adiponectin, leptin or the A/L ratio were compared. RESULTS: Basal lipolysis was similar between groups. Women with a low plasma A/L ratio were characterized by higher adiposity and larger SCABD and OME adipocytes (p<0.01) compared to those with a high ratio. In OME adipocytes, women in the low adiponectinemia tertile showed higher isoproterenol-stimulated lipolysis (0.01

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.

Hypoabsorptive surgeries cause limb-dependent changes in the gut endocannabinoidome and microbiome in association with beneficial metabolic effects.

OBJECTIVE: To determine whether the metabolic benefits of hypoabsorptive surgeries are associated with changes in the gut endocannabinoidome (eCBome) and microbiome. METHODS: Biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) were performed in diet-induced obese (DIO) male Wistar rats. Control groups fed a high-fat diet (HF) included sham-operated (SHAM HF) and SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW). Body weight, fat mass gain, fecal energy loss, HOMA-IR, and gut-secreted hormone levels were measured. The levels of eCBome lipid mediators and prostaglandins were quantified in different intestinal segments by LC-MS/MS, while expression levels of genes encoding eCBome metabolic enzymes and receptors were determined by RT-qPCR. Metataxonomic (16S rRNA) analysis was performed on residual distal jejunum, proximal jejunum, and ileum contents. RESULTS: BPD-DS and SADI-S reduced fat gain and HOMA-IR, while increasing glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) levels in HF-fed rats. Both surgeries induced potent limb-dependent alterations in eCBome mediators and in gut microbial ecology. In response to BPD-DS and SADI-S, changes in gut microbiota were significantly correlated with those of eCBome mediators. Principal component analyses revealed connections between PYY, N-oleoylethanolamine (OEA), N-linoleoylethanolamine (LEA), Clostridium, and Enterobacteriaceae_g_2 in the proximal and distal jejunum and in the ileum. CONCLUSIONS: BPD-DS and SADI-S caused limb-dependent changes in the gut eCBome and microbiome. The present results indicate that these variables could significantly influence the beneficial metabolic outcome of hypoabsorptive bariatric surgeries.

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.

Validation of the Fatty Liver Index for identifying non-alcoholic fatty liver disease in a Kenyan population.

BACKGROUND AND AIM: Fatty Liver Index (FLI) is a simple clinical scoring system estimating non-alcoholic fatty liver disease (NAFLD). It is validated in European-descent and Asian populations, but not in sub-Saharan Africans. The aim of this study is to evaluate the validity of the FLI for predicting NAFLD in a population from Kenya. METHODS: Participants were recruited from a community-based study conducted in Kenya. NAFLD was diagnosed using hepatic ultrasonography. Clinical, anthropometrical, biochemical and lifestyle data were obtained. The accuracy and cut-off point of the FLI to detect NAFLD were evaluated by area under the receiver operator characteristic curve and the maximum Youden index analysis. RESULTS: A total of 640 participants (94 with NAFLD) were included. Mean age was 37.4 ± 0.4 years and 58.7% were women. Mean body mass index (BMI) was 22.3 ± 0.2 kg/m2 and waist circumference (WC) 79.1 ± 0.4 cm. A total of 15 (2.3%) participants were diagnosed with type 2 diabetes and 65 (10.2%) with obesity (BMI ≥ 30 kg/m2 ). AUROC of FLI for predicting NAFLD was 0.80 (95% CI 0.74-0.85), which was significantly higher compared to individual components gamma-glutamyl transferase and triglycerides (p < 0.05), but not compared to anthropometric parameters BMI (AUROC of 0.83, 95% CI 0.79-0.88) and WC (AUROC of 0.81, 95% CI 0.76-0.87). CONCLUSIONS: FLI is a simple valid scoring system to use in rural and urban Kenyan adults. However, this index might not be superior to BMI or WC to predict NAFLD, and those measurements might therefore be more appropriate in limited settings.

First-trimester diet quality in association with maternal subcutaneous and visceral adipose tissue thicknesses and glucose homeostasis during pregnancy.

We aimed to characterise the associations between first-trimester diet quality, adiposity, and glucose homeostasis measurements throughout pregnancy in a sample of 104 healthy pregnant women. Three Web-based 24-h recalls were completed, from which the Alternate Healthy Eating Index (AHEI) was calculated. At each trimester (12.5 ± 0.7, 22.8 ± 1.0, and 33.6 ± 1.3 weeks of gestation), fasting glucose and insulin were measured to compute an insulin resistance index (HOMA-IR). Subcutaneous and visceral adipose tissue thicknesses were estimated by ultrasound at the end of the first trimester. Inverse associations were observed between the first-trimester AHEI and first-trimester fasting insulin (r = 0.24; p < 0.05), and HOMA-IR (r = -0.22; p < 0.05), as well as third-trimester fasting insulin (r = -0.20; p < 0.05). A trend was also observed between first-trimester AHEI and first-trimester SAT thickness (r = -0.17; p < 0.1). Pre- and early-pregnancy adiposity measurements were identified as high predictors fasting insulin concentrations throughout pregnancy. Higher early-pregnancy diet quality is associated with more favourable metabolic measurements during pregnancy.

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.

Consistent gut bacterial and short-chain fatty acid signatures in hypoabsorptive bariatric surgeries correlate with metabolic benefits in rats.

OBJECTIVE: The study aimed at comparing how changes in the gut microbiota are associated to the beneficial effects of the most clinically efficient hypoabsorptive bariatric procedures, namely Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S). METHODS: Diet-induced obese (DIO) male Wistar rats were divided into seven groups. In addition to the groups subjected to RYGB, BPD-DS and SADI-S, the following four control groups were included: SHAM-operated rats fed a high-fat diet (SHAM HF), SHAM fed a low-fat diet (SHAM LF), SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW) and sleeve-gastrectomy (SG) rats. Body weight, food intake, glucose tolerance, insulin sensitivity/resistance, and L-cell secretion were assessed. The gut microbiota (16 S ribosomal RNA gene sequencing) as well as the fecal and cæcal contents of short-chain fatty acids (SCFAs) were also analyzed prior to, and after the surgeries. RESULTS: The present study demonstrates the beneficial effect of RYGB, BPD-DS and SADI-S on fat mass gain and glucose metabolism in DIO rats. These benefits were proportional to the effect of the surgeries on food digestibility (BPD-DS > SADI-S > RYGB). Notably, hypoabsorptive surgeries led to consonant microbial signatures characterized by decreased abundance of the Ruminococcaceae (Oscillospira and Ruminococcus), Oscillospiraceae (Oscillibacter) and Christensenellaceae, and increased abundance of the Clostridiaceae (Clostridium), Sutterellaceae (Sutterella) and Enterobacteriaceae. The gut bacteria following hypoabsorptive surgeries were associated with higher fecal levels of propionate, butyrate, isobutyrate and isovalerate. Increases in the fecal SCFAs were in turn positively and strongly correlated with the levels of peptide tyrosine-tyrosine (PYY) and with the beneficial effects of the surgery. CONCLUSION: The present study emphasizes the consistency with which the three major hypoabsorptive bariatric procedures RYGB, BPD-DS and SADI-S create a gut microbial environment capable of producing a SCFA profile favorable to the secretion of PYY and to beneficial metabolic effects.

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.

Large-scale analysis of circulating glutamate and adipose gene expression in relation to abdominal obesity.

Circulating levels of the amino acid glutamate are associated with central fat accumulation, yet the pathophysiology of this relationship remains unknown. We aimed to (i) refine and validate the association between circulating glutamate and abdominal obesity in a large twin cohort, and (ii) investigate whether transcriptomic profiles in adipose tissue could provide insight into the biological mechanisms underlying the association. First, in a cohort of 4665 individuals from the TwinsUK resource, we identified individuals with abdominal obesity and compared prevalence of the latter across circulating glutamate quintiles. Second, we used transcriptomic signatures generated from adipose tissue, both subcutaneous and visceral, to investigate associations with circulating glutamate levels. Individuals in the top circulating glutamate quintile had a sevenfold higher prevalence of abdominal obesity compared to those in the bottom quintile. The adipose tissue transcriptomic analyses identified GLUL, encoding Glutamate-Ammonia Ligase, as being associated with circulating glutamate and abdominal obesity, with pronounced signatures in the visceral depot. In conclusion, circulating glutamate is positively associated with the prevalence of abdominal obesity which relates to dysregulated GLUL expression specifically in visceral adipose tissue.

Obesity Phenotypes, Diabetes, and Cardiovascular Diseases.

This review addresses the interplay between obesity, type 2 diabetes mellitus, and cardiovascular diseases. It is proposed that obesity, generally defined by an excess of body fat causing prejudice to health, can no longer be evaluated solely by the body mass index (expressed in kg/m2) because it represents a heterogeneous entity. For instance, several cardiometabolic imaging studies have shown that some individuals who have a normal weight or who are overweight are at high risk if they have an excess of visceral adipose tissue-a condition often accompanied by accumulation of fat in normally lean tissues (ectopic fat deposition in liver, heart, skeletal muscle, etc). On the other hand, individuals who are overweight or obese can nevertheless be at much lower risk than expected when faced with excess energy intake if they have the ability to expand their subcutaneous adipose tissue mass, particularly in the gluteal-femoral area. Hence, excessive amounts of visceral adipose tissue and of ectopic fat largely define the cardiovascular disease risk of overweight and moderate obesity. There is also a rapidly expanding subgroup of patients characterized by a high accumulation of body fat (severe obesity). Severe obesity is characterized by specific additional cardiovascular health issues that should receive attention. Because of the difficulties of normalizing body fat content in patients with severe obesity, more aggressive treatments have been studied in this subgroup of individuals such as obesity surgery, also referred to as metabolic surgery. On the basis of the above, we propose that we should refer to obesities rather than obesity.

Dietary intakes in pregnant women with previous bariatric surgery.

PURPOSE: To (1) assess dietary intakes of pregnant women with previous bariatric surgery in comparison with Dietary Reference Intakes (DRIs); (2) compare their dietary intakes as well as their diet quality with a control group of pregnant women with no history of bariatric surgery. METHODS: Twenty-eight (28) pregnant women with previous surgery (sleeve gastrectomy, n = 7 and biliopancreatic diversion with duodenal switch, n = 21) were matched for pre-pregnancy body mass index with 28 pregnant women with no history of bariatric surgery. In at least one trimester, participants completed a minimum of 2 Web-based 24-h dietary recalls from which energy, macro- and micronutrient intakes as well as the Canadian Healthy Eating Index (C-HEI) were derived. RESULTS: No differences were observed for energy intake between groups. All women had protein intakes within the recommended range, but most women with previous surgery had carbohydrate (67%) and dietary fiber intakes (98%) below recommendations. In both groups, mean total fat, saturated fatty acids, free sugars and sodium intakes were above recommendations, as opposed to mean vitamin D, folic acid and iron dietary intakes below recommendations for most women. Compared with the control group, pregnant women with previous bariatric surgery had lower overall C-HEI scores. CONCLUSION: These results suggest that pregnant women with previous bariatric surgery would benefit from a nutritional follow-up throughout their pregnancy. LEVEL OF EVIDENCE: III: Evidence obtained from well-designed cohort or case-control analytic studies.

Spontaneous neural activity changes after bariatric surgery: A resting-state fMRI study.

BACKGROUND: Metabolic disorders associated with obesity could lead to alterations in brain structure and function. Whether these changes can be reversed after weight loss is unclear. Bariatric surgery provides a unique opportunity to address these questions because it induces marked weight loss and metabolic improvements which in turn may impact the brain in a longitudinal fashion. Previous studies found widespread changes in grey matter (GM) and white matter (WM) after bariatric surgery. However, findings regarding changes in spontaneous neural activity following surgery, as assessed with the fractional amplitude of low frequency fluctuations (fALFF) and regional homogeneity of neural activity (ReHo), are scarce and heterogenous. In this study, we used a longitudinal design to examine the changes in spontaneous neural activity after bariatric surgery (comparing pre- to post-surgery), and to determine whether these changes are related to cardiometabolic variables. METHODS: The study included 57 participants with severe obesity (mean BMI=43.1 ± 4.3 kg/m2) who underwent sleeve gastrectomy (SG), biliopancreatic diversion with duodenal switch (BPD), or Roux-en-Y gastric bypass (RYGB), scanned prior to bariatric surgery and at follow-up visits of 4 months (N = 36), 12 months (N = 29), and 24 months (N = 14) after surgery. We examined fALFF and ReHo measures across 1022 cortical and subcortical regions (based on combined Schaeffer-Xiao parcellations) using a linear mixed effect model. Voxel-based morphometry (VBM) based on T1-weighted images was also used to measure GM density in the same regions. We also used an independent sample from the Human Connectome Project (HCP) to assess regional differences between individuals who had normal-weight (N = 46) or severe obesity (N = 46). RESULTS: We found a global increase in the fALFF signal with greater increase within dorsolateral prefrontal cortex, precuneus, inferior temporal gyrus, and visual cortex. This effect was more significant 4 months after surgery. The increase within dorsolateral prefrontal cortex, temporal gyrus, and visual cortex was more limited after 12 months and only present in the visual cortex after 24 months. These increases in neural activity measured by fALFF were also significantly associated with the increase in GM density following surgery. Furthermore, the increase in neural activity was significantly related to post-surgery weight loss and improvement in cardiometabolic variables, such as blood pressure. In the independent HCP sample, normal-weight participants had higher global and regional fALFF signals, mainly in dorsolateral/medial frontal cortex, precuneus and middle/inferior temporal gyrus compared to the obese participants. These BMI-related differences in fALFF were associated with the increase in fALFF 4 months post-surgery especially in regions involved in control, default mode and dorsal attention networks. CONCLUSIONS: Bariatric surgery-induced weight loss and improvement in metabolic factors are associated with widespread global and regional increases in neural activity, as measured by fALFF signal. These findings alongside the higher fALFF signal in normal-weight participants compared to participants with severe obesity in an independent dataset suggest an early recovery in the neural activity signal level after the surgery.

Associations between markers of mammary adipose tissue dysfunction and breast cancer prognostic factors.

BACKGROUND: Obesity fosters worse clinical outcomes in both premenopausal and postmenopausal women with breast cancer. Emerging evidence suggests that an android body fat distribution in particular is deleterious for breast cancer prognosis. The extent of adipose tissue dysfunction, especially how it relates to breast cancer prognostic factors and anthropometric measurements, has not been fully investigated. OBJECTIVE: Our objective was to examine if markers of adipose tissue dysfunction, such as hypertrophy and macrophage accumulation, are relevant for the pathophysiology of breast cancer and its associated prognostic factors in a well-characterised cohort of women with breast cancer who did not receive treatment before surgery. METHODS: A consecutive series of 164 women with breast cancer provided breast adipose tissue sample. Multivariate generalised linear models were used to test associations of anthropometric indices and prognostic factors with markers of adipose tissue dysfunction. RESULTS: We found associations of breast adipocyte size and macrophage infiltration (number of CD68+ cells/100 adipocytes) with adiposity, particularly a strong association between breast adipocyte size and central obesity, independent of total adiposity, age and menopausal status (ßadj = 0.87; p = 0.0001). We also identified relationships of adipocyte hypertrophy and macrophage infiltration with prognostic factors, such as cancer stage and tumour grade (p < 0.05). RNA expression of pro-inflammatory cytokines (IL6, TNF) and leptin was also increased as a function of adipocyte size and CD86+/CD11c+ macrophage number/100 adipocytes (p < 0.05). CONCLUSIONS: Our findings support the model of dysfunctional adipose tissue in obesity-associated breast cancer.

Pathophysiology of human visceral obesity: an update.

Excess intra-abdominal adipose tissue accumulation, often termed visceral obesity, is part of a phenotype including dysfunctional subcutaneous adipose tissue expansion and ectopic triglyceride storage closely related to clustering cardiometabolic risk factors. Hypertriglyceridemia; increased free fatty acid availability; adipose tissue release of proinflammatory cytokines; liver insulin resistance and inflammation; increased liver VLDL synthesis and secretion; reduced clearance of triglyceride-rich lipoproteins; presence of small, dense LDL particles; and reduced HDL cholesterol levels are among the many metabolic alterations closely related to this condition. Age, gender, genetics, and ethnicity are broad etiological factors contributing to variation in visceral adipose tissue accumulation. Specific mechanisms responsible for proportionally increased visceral fat storage when facing positive energy balance and weight gain may involve sex hormones, local cortisol production in abdominal adipose tissues, endocannabinoids, growth hormone, and dietary fructose. Physiological characteristics of abdominal adipose tissues such as adipocyte size and number, lipolytic responsiveness, lipid storage capacity, and inflammatory cytokine production are significant correlates and even possible determinants of the increased cardiometabolic risk associated with visceral obesity. Thiazolidinediones, estrogen replacement in postmenopausal women, and testosterone replacement in androgen-deficient men have been shown to favorably modulate body fat distribution and cardiometabolic risk to various degrees. However, some of these therapies must now be considered in the context of their serious side effects. Lifestyle interventions leading to weight loss generally induce preferential mobilization of visceral fat. In clinical practice, measuring waist circumference in addition to the body mass index could be helpful for the identification and management of a subgroup of overweight or obese patients at high cardiometabolic risk.

Neuroanatomical changes in white and grey matter after sleeve gastrectomy.

BACKGROUND: MRI studies show that obese adults have reduced grey matter (GM) and white matter (WM) tissue density as well as altered WM integrity. Bariatric surgery can lead to substantial weight loss and improvements in metabolic parameters, but it remains to be examined if it induces structural brain changes. The aim of this study was to characterize GM and WM density changes measured with MRI in a longitudinal setting following sleeve gastrectomy, and to determine whether any changes are related to inflammation and cardiometabolic blood markers. METHODS: 29 participants with obesity (age: 45.9 â€‹± â€‹7.8 years) scheduled to undergo sleeve gastrectomy were recruited. High-resolution T1-weighted anatomical images were acquired 1 month prior to as well as 4 and 12 months after surgery. GM and WM densities were quantified using voxel-based morphometry (VBM). Circulating lipid profile, glucose, insulin and inflammatory markers (interleukin-6, C-reactive protein and lipopolysaccharide-binding protein) were measured at each time point. A linear mixed effect model was used to compare brain changes before and after SG, controlling for age, sex, initial BMI and diabetic status. To assess the associations between changes in adiposity, metabolism and inflammation and changes in GM or WM density, the mean GM and WM densities were extracted across all the participants using atlas-derived regions of interest, and linear mixed-effect models were used. RESULTS: As expected, weight, BMI, waist circumference and neck circumference significantly decreased after SG compared with baseline (p â€‹< â€‹0.001 for all). A widespread increase in WM density was observed after surgery, particularly in the cerebellum, brain stem, cerebellar peduncle, cingulum, corpus callosum and corona radiata (p â€‹< â€‹0.05, after FDR correction). Significant increases in GM density were observed 4 months after SG compared to baseline in several brain regions such as the bilateral occipital cortex, temporal cortex, postcentral gyrus, cerebellum, hippocampus and insula as well as right fusiform gyrus, right parahippocampal gyrus, right lingual gyrus and right amygdala. These GM and WM increases were more pronounced and widespread after 12 months and were significantly associated with post-operative weight loss and the improvement of metabolic alterations. A linear mixed-effect model also showed associations between post-operative reductions in lipopolysaccharide-binding protein, a marker of inflammation, and increased WM density. To confirm our results, we tested whether the peak of each significant region showed BMI-related differences in an independent dataset (Human Connectome Project). We matched a group of individuals who were severely obese with a group of individuals who were lean for age, sex and ethnicity. Severe obesity was associated with reduced WM density in the brain stem and cerebellar peduncle as well as reduced GM density in cerebellum, regions that significantly changed after surgery (p â€‹< â€‹0.01 for all clusters). CONCLUSIONS: Bariatric surgery-induced weight loss and improvement in metabolic alterations is associated with widespread increases in WM and GM densities. These post-operative changes overlapped with baseline brain differences between participants who were severely obese and those who were normal-weight in a separate dataset, which may suggest a recovery of WM and GM alterations after bariatric surgery.

Measurement of bioactive osteocalcin in humans using a novel immunoassay reveals association with glucose metabolism and ß-cell function.

Osteocalcin (OCN) is a bone-derived hormone involved in the regulation of glucose metabolism. In serum, OCN exists in carboxylated and uncarboxylated forms (ucOCN), and studies in rodents suggest that ucOCN is the bioactive form of this hormone. Whether this is also the case in humans is unclear, because a reliable assay to measure ucOCN is not available. Here, we established and validated a new immunoassay (ELISA) measuring human ucOCN and used it to determine the level of bioactive OCN in two cohorts of overweight or obese subjects, with or without type 2 diabetes (T2D). The ELISA could specifically detect ucOCN concentrations ranging from 0.037 to 1.8 ng/mL. In a first cohort of overweight or obese postmenopausal women without diabetes (n = 132), ucOCN correlated negatively with fasting glucose (r = -0.18, P = 0.042) and insulin resistance assessed by the homeostatic model assessment of insulin resistance (r = -0.18, P = 0.038) and positively with insulin sensitivity assessed by a hyperinsulinemic-euglycemic clamp (r = 0.18, P = 0.043) or insulin sensitivity index derived from an oral glucose tolerance test (r = 0.26, P = 0.003). In a second cohort of subjects with severe obesity (n = 16), ucOCN was found to be lower in subjects with T2D compared with those without T2D (2.76 ± 0.38 versus 4.52 ± 0.06 ng/mL, P = 0.009) and to negatively correlate with fasting glucose (r = -0.50, P = 0.046) and glycated hemoglobin (r = -0.57, P = 0.021). Moreover, the subjects with ucOCN levels below 3 ng/mL had a reduced insulin secretion rate during a hyperglycemic clamp (P = 0.03). In conclusion, ucOCN measured with this novel and specific assay is inversely associated with insulin resistance and ß-cell dysfunction in humans.

Characterization of a Coproduct from the Sea Cucumber Cucumaria frondosa and Its Effects on Visceral Adipocyte Size in Male Wistar Rats.

Sea cucumbers have been shown to have potential health benefits and are a rich source of several bioactive compounds, particularly triterpenoid saponins. However, most studies concentrate on the body wall, and little is known about the health effects of the coproducts. The objectives of this study were to determine the nutritional composition of a coproduct from the sea cucumber Cucumaria frondosa and the effects of the dietary consumption of this coproduct on cardiometabolic health in rats. Chemical, biochemical, and nutritional analyses were performed to characterize this coproduct. Forty (40) male Wistar rats were then equally divided into four groups and fed a purified control diet or a diet enriched with 0.5%, 1.5%, or 2.5% (by protein) of coproduct. After 28 days of feeding, the rats were sacrificed. Body and tissue weight, body composition, epididymal adipocyte diameter, plasma and hepatic lipids, glycemia, and insulinemia were measured at the end of the 28-day experiment. Analysis of the coproduct revealed high levels of protein, omega-3 fatty acids, minerals, and saponins. The 1.5% group had significantly smaller epididymal adipocytes vs. the control. We conclude that dietary administration of this sea cucumber coproduct at 1.5% doses decreases visceral adiposity, potentially decreasing the risk of cardiometabolic dysfunction. The coproduct's saponin content may contribute to the observed effects, but the impact of other components cannot be ruled out.