Cohort profile: study design and baseline characteristics of an observational longitudinal weight loss cohort and biorepository of patients undergoing sleeve gastrectomy in the USA.

PURPOSE: We developed a comprehensive sleeve gastrectomy (SG) weight loss study cohort and biorepository to uncover mechanisms, biomarkers and predictive factors of weight loss, weight maintenance and amelioration of obesity-related comorbidities. For this purpose, we collected psychosocial, anthropometric, clinical data and a variety of samples pre-surgery, intraoperatively and 1.5, 3, 12 and 24 months post-surgery. For longer-term assessment, the collection of psychosocial and anthropometric data was extended to 10 years. Here, we present in-depth characterisation of the cohort and detailed overview of study procedures as a foundation for future analyses. PARTICIPANTS: We consented 647 participants between June 2017 and March 2020 from two bariatric surgery clinics in New York City-one major urban hospital and one private hospital. Of 355 participants who provided baseline data, 300 underwent SG. Of these, 79% are females with an average age of 38 years, 68% are Hispanic, 20% are non-Hispanic Black and 11% are non-Hispanic White. FINDINGS TO DATE: We collected intraoperative adipose and stomach tissues from 282 patients and biosamples (blood, urine, saliva, stool) from 245 patients at 1.5 months, 238 at 3 month, 218 at 12 months and 180 at 24 months post-surgery. We are currently collecting anthropometric and psychosocial data annually until 10 years post-surgery. Data analysis is currently underway. FUTURE PLANS: Our future research will explore the variability in weight loss outcomes observed in our cohort, particularly among Black and Hispanic patients in comparison to their White counterparts. We will identify social determinants of health, metabolic factors and other variables that may predict weight loss success, weight maintenance and remission of obesity-related comorbidities. Additionally, we plan to leverage our biorepository for collaborative research studies. We will complete long-term follow-up data by December 2031. We plan to apply for funding to expand biosample collection through year 10 to provide insights into the mechanisms of long-term weight maintenance.

Continuous glucose monitoring captures glycemic variability in obesity after sleeve gastrectomy: A prospective cohort study.

Objective: HbA1c is an insensitive marker for assessing real-time dysglycemia in obesity. This study investigated whether 1-h plasma glucose level (1-h PG) ≥155 mg/dL (8.6 mmol/L) during an oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) measurement of glucose variability (GV) better reflected dysglycemia than HbA1c after weight loss from metabolic and bariatric surgery. Methods: This was a prospective cohort study of 10 participants with type 2 diabetes compared with 11 participants with non-diabetes undergoing sleeve gastrectomy (SG). At each research visit; before SG, and 6 weeks and 6 months post-SG, body weight, fasting lipid levels, and PG and insulin concentrations during an OGTT were analyzed. Mean amplitude of glycemic excursions (MAGE), a CGM-derived GV index, was analyzed. Results: The 1-h PG correlated with insulin resistance markers, triglyceride/HDL ratio and triglyceride glucose index in both groups before surgery. At 6 months, SG caused 22% weight loss in both groups. Despite a reduction in HbA1c by 3.0 ± 1.3% in the diabetes group (p < 0.01), 1-h PG, and MAGE remained elevated, and the oral disposition index, which represents pancreatic ß-cell function, remained reduced in the diabetes group when compared to the non-diabetes group. Conclusions: Elevation of GV markers and reduced disposition index following SG-induced weight loss in the diabetes group underscores persistent ß-cell dysfunction and the potential residual risk of diabetes complications.

Obesity Duration and Cardiometabolic Disease.

Cardiovascular disease risk is known to be influenced by both the severity of a risk factor and the duration of exposure (eg, LDL [low-density lipoprotein] cholesterol, tobacco smoke). However, this concept has been largely neglected within the obesity literature. While obesity severity has been closely linked with cardiometabolic diseases, the risk of developing these conditions among those with obesity may be augmented by greater obesity duration over the life span. Few longitudinal or contemporary studies have investigated the influence of both factors in combination-cumulative obesity exposure-instead generally focusing on obesity severity, often at a single time point, given ease of use and lack of established methods to encapsulate duration. Our review focuses on what is known about the influence of the duration of exposure to excess adiposity within the obesity-associated cardiometabolic disease risk equation by means of summarizing the hypothesized mechanisms for and evidence surrounding the relationships of obesity duration with diverse cardiovascular and metabolic disease. Through the synthesis of the currently available data, we aim to highlight the importance of a better understanding of the influence of obesity duration in cardiovascular and metabolic disease pathogenesis. We underscore the clinical importance of aggressive early attention to obesity identification and intervention to prevent the development of chronic diseases that arise from exposure to excess body weight.

Body Weight and Prandial Variation of Plasma Metabolites in Subjects Undergoing Gastric Band-Induced Weight Loss.

BACKGROUND: Bariatric procedures are safe and effective treatments for obesity, inducing rapid and sustained loss of excess body weight. Laparoscopic adjustable gastric banding (LAGB) is unique among bariatric interventions in that it is a reversible procedure in which normal gastrointestinal anatomy is maintained. Knowledge regarding how LAGB effects change at the metabolite level is limited. OBJECTIVES: To delineate the impact of LAGB on fasting and postprandial metabolite responses using targeted metabolomics. SETTING: Individuals undergoing LAGB at NYU Langone Medical Center were recruited for a prospective cohort study. METHODS: We prospectively analyzed serum samples from 18 subjects at baseline and 2 months after LAGB under fasting conditions and after a 1-hour mixed meal challenge. Plasma samples were analyzed on a reverse-phase liquid chromatography time-of-flight mass spectrometry metabolomics platform. The main outcome measure was their serum metabolite profile. RESULTS: We quantitatively detected over 4,000 metabolites and lipids. Metabolite levels were altered in response to surgical and prandial stimuli, and metabolites within the same biochemical class tended to behave similarly in response to either stimulus. Plasma levels of lipid species and ketone bodies were statistically decreased after surgery whereas amino acid levels were affected more by prandial status than surgical condition. CONCLUSIONS: Changes in lipid species and ketone bodies postoperatively suggest improvements in the rate and efficiency of fatty acid oxidation and glucose handling after LAGB. Further investigation is necessary to understand how these findings relate to surgical response, including long term weight maintenance, and obesity-related comorbidities such as dysglycemia and cardiovascular disease.

Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation.

Although tissue uptake of fatty acids from chylomicrons is primarily via lipoprotein lipase (LpL) hydrolysis of triglycerides (TGs), studies of patients with genetic LpL deficiency suggest additional pathways deliver dietary lipids to tissues. Despite an intact endothelial cell (EC) barrier, hyperchylomicronemic patients accumulate chylomicron-derived lipids within skin macrophages, leading to the clinical finding eruptive xanthomas. We explored whether an LpL-independent pathway exists for transfer of circulating lipids across the EC barrier. We found that LpL-deficient mice had a marked increase in aortic EC lipid droplets before and after a fat gavage. Cultured ECs internalized chylomicrons, which were hydrolyzed within lysosomes. The products of this hydrolysis fueled lipid droplet biogenesis in ECs and triggered lipid accumulation in cocultured macrophages. EC chylomicron uptake was inhibited by competition with HDL and knockdown of the scavenger receptor-BI (SR-BI). In vivo, SR-BI knockdown reduced TG accumulation in aortic ECs and skin macrophages of LpL-deficient mice. Thus, ECs internalize chylomicrons, metabolize them in lysosomes, and either store or release their lipids. This latter process may allow accumulation of TGs within skin macrophages and illustrates a pathway that might be responsible for creation of eruptive xanthomas.

Obesity and ethnicity alter gene expression in skin.

Obesity is accompanied by dysfunction of many organs, but effects on the skin have received little attention. We studied differences in epithelial thickness by histology and gene expression by Affymetrix gene arrays and PCR in the skin of 10 obese (BMI 35-50) and 10 normal weight (BMI 18.5-26.9) postmenopausal women paired by age and ethnicity. Epidermal thickness did not differ with obesity but the expression of genes encoding proteins associated with skin blood supply and wound healing were altered. In the obese, many gene expression pathways were broadly downregulated and subdermal fat showed pronounced inflammation. There were no changes in skin microbiota or metabolites. African American subjects differed from European Americans with a trend to increased epidermal thickening. In obese African Americans, compared to obese European Americans, we observed altered gene expression that may explain known differences in water content and stress response. African Americans showed markedly lower expression of the gene encoding the cystic fibrosis transmembrane regulator characteristic of the disease cystic fibrosis. The results from this preliminary study may explain the functional changes found in the skin of obese subjects and African Americans.

Lipoprotein insulin resistance score in nondiabetic patients with obesity after bariatric surgery.

BACKGROUND: Lipoprotein insulin resistance (LPIR) score is a composite biomarker representative of atherogenic dyslipidemia characteristic of early insulin resistance. It is elevated in obesity and may provide information not captured in glycosylated hemoglobin and homeostatic model assessment for insulin resistance. While bariatric surgery reduces diabetes incidence and resolves metabolic syndrome, the effect of bariatric surgery on LPIR is untested. OBJECTIVES: We sought to assess the effects of Roux-en-Y gastric bypass and sleeve gastrectomy on LPIR in nondiabetic women with obesity. SETTING: Nonsmoking, nondiabetic, premenopausal Hispanic women, age ≥18 years, undergoing Roux-en-Y gastric bypass or sleeve gastrectomy at Bellevue Hospital were recruited for a prospective observational study. METHODS: Anthropometric measures and blood sampling were performed preoperatively and at 6 and 12 months postoperatively. LPIR was measured by nuclear magnetic resonance spectroscopy. RESULTS: Among 53 women (Roux-en-Y gastric bypass, n = 22; sleeve gastrectomy, n = 31), mean age was 32 ± 7 years and body mass index 44.1 ± 6.4 kg/m2. LPIR was reduced by 35 ± 4% and 46 ± 4% at 6 and 12 months after surgery, respectively, with no difference by procedure. Twenty-seven of 53 patients met International Diabetes Federation criteria for metabolic syndrome preoperatively and had concomitant higher homeostatic model assessment for insulin resistance, glycosylated hemoglobin, nonhigh-density lipoprotein-cholesterol and LPIR. Twenty-five of 27 patients experienced resolution of metabolic syndrome postoperatively. Concordantly, the preoperative differences in homeostatic model assessment for insulin resistance, glycosylated hemoglobin, and nonhigh-density lipoprotein-cholesterol between those with and without metabolic syndrome resolved at 6 and 12 months. In contrast, patients with metabolic syndrome preoperatively exhibited greater LPIR scores at 6 and 12 months postoperatively. CONCLUSION: This is the first study to demonstrate improvement in insulin resistance, as measured by LPIR, after bariatric surgery with no difference by procedure. This measure, but not traditional markers, was persistently higher in patients with a preoperative metabolic syndrome diagnosis, despite resolution of the condition.

Treatment of Obesity in Mitigating Metabolic Risk.

Through diverse mechanisms, obesity contributes to worsened cardiometabolic health and increases rates of cardiovascular events. Effective treatment of obesity is necessary to reduce the associated burdens of diabetes mellitus, cardiovascular disease, and death. Despite increasing cardiovascular outcome data on obesity interventions, only a small fraction of the population with obesity are optimally treated. This is a primary impetus for this article in which we describe the typical weight loss, as well as the associated impact on both traditional and novel cardiovascular disease risk factors, provided by the 4 primary modalities for obtaining weight loss in obesity-dietary modification, increasing physical activity, pharmacotherapy, and surgery. We also attempt to highlight instances where changes in metabolic risk are relatively specific to particular interventions and appear at least somewhat independent of weight loss. Finally, we suggest important areas for further research to reduce and prevent adverse cardiovascular consequences due to obesity.

The effects of trans-resveratrol on insulin resistance, inflammation, and microbiota in men with the metabolic syndrome: A pilot randomized, placebo-controlled clinical trial.

BACKGROUND AND AIM: The metabolic syndrome (MetS) is a pathological condition comprised of abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. It has become a major threat globally, resulting in rapidly increasing rates of diabetes, coronary heart disease, and stroke. The polyphenol resveratrol (RES) is believed to improve glucose homeostasis and insulin resistance by activating sirtuin, which acetylates and coactivates downstream targets and affects glucose and lipid homeostasis in the liver, insulin secretion in the pancreas, and glucose uptake in skeletal muscle. We studied the effects of RES on insulin resistance, glucose homeostasis, and concomitant effects on adipose tissue metabolism and fecal microbiota in insulin-resistant subjects with the MetS. METHODS: A total of 28 obese men with the MetS were studied during a 35-day stay in the Rockefeller University Hospital metabolic unit. Subjects were randomized to receive RES 1 g orally twice daily or placebo while kept weight stable and consuming a western-style diet. At baseline, and after 30 days of RES or placebo administration, subjects underwent testing that included a euglycemic, hyperinsulinemic clamp, 2-h oral glucose tolerance test (GTT), resting energy expenditure, daily blood pressure monitoring, abdominal adipose tissue biopsy, and fecal and blood collections. RESULTS: RES induced no changes in insulin resistance but reduced the 120-min time point and the area under the curve for glucose concentration in the 2-h GTT. In post-hoc analysis, Caucasian subjects showed a significant improvement in insulin sensitivity and glucose homeostasis after GTT, whereas non-Caucasians showed no similar effects. Levels of fasting plasma RES and its primary metabolite dihydroresveratrol were variable and did not explain the racial differences in glucose homeostasis. RES administration to Caucasian subjects leads to an increase in several taxa including Akkermansia muciniphila. CONCLUSIONS: RES 2 g administered orally to obese men with MetS and insulin resistance marginally altered glucose homeostasis. However, in a small group of Caucasians, insulin resistance and glucose homeostasis improved. No concomitant changes in adipose tissue metabolism occurred, but fecal microbiota showed RES-induced changes. RELEVANCE FOR PATIENTS: The MetS increases the risk of diabetes, heart disease, and stroke. A major component of the syndrome is insulin resistance, resulting in systemic inflammation and hyperinsulinemia. The primary treatment consists of lifestyle changes, improved diet, and increased physical activity. This is often unsuccessful. In this study, RES was well tolerated. In Caucasian men, it significantly improved insulin sensitivity and glucose homeostasis. Similar results were found in studies that consisted exclusively of Caucasian men. However, RES presents a novel addition to the current treatment of the MetS and its sequelae.

Circulating MIR148A associates with sensitivity to adiponectin levels in human metabolic surgery for weight loss

Objective: We sought to discover secreted biomarkers to monitor the recovery of physiological adiponectin levels with metabolic surgery, focusing on epigenetic changes that might predict adiponectin function. Design: We conducted a prospective observational study of patients undergoing metabolic surgery by Roux-en-Y Gastric Bypass (RYGB) for weight loss in a single center (IRB GHS # 1207-27). Methods: All patients (n = 33; 27 females; 6 males) signed informed consent. Metabolites, adiponectin and MIR148A were measured in fasting plasma. We followed MIQE for transcript profiles. Results: Patients lost on average 47 ± 12% excess BMI (%EBMI) after 12 weeks. Adiponectin pre, post or delta (post minus pre) did not correlate with %EBMIL. A decrease in adiponectin following weight loss surgery was observed in a subset of patients, chi-square test of independence rejects the null hypotheses that the liver DNA methyltransferase 1 (DNMT1) and delta adiponectin are independent (chi-square statistics χ2 = 6.9205, P = 0.00852, n = 33), as well as MIR148A and delta adiponectin are independent (chi-square statistics χ2 = 9.6823, P = 0.00186, n = 33). The presence of plasma MIR148A allows identification of patients that appear to be adiponectin insensitive at baseline. Conclusion: We combined the presence of plasma MIR148A, the concentration of total adiponectin and the expression of DNA methyltransferase 1 (DNMT1) in liver biopsy tissue to identify patients with non-physiological adiponectin. Weight loss and physical activity interventions complemented with the new method presented here could serve to monitor the physiological levels of adiponectin, thought to be important for long-term weight loss maintenance.

Effects of Rapid Weight Loss on Systemic and Adipose Tissue Inflammation and Metabolism in Obese Postmenopausal Women.

CONTEXT: Obesity is associated with subclinical white adipose tissue inflammation, as defined by the presence of crown-like structures (CLSs) consisting of dead or dying adipocytes encircled by macrophages. In humans, bariatric surgery-induced weight loss leads to a decrease in CLSs, but the effects of rapid diet-induced weight loss on CLSs and metabolism are unclear. OBJECTIVE: To determine the effects of rapid very-low-calorie diet-induced weight loss on CLS density, systemic biomarkers of inflammation, and metabolism in obese postmenopausal women. DESIGN: Prospective cohort study. SETTING: Rockefeller University Hospital, New York, NY. PARTICIPANTS: Ten obese, postmenopausal women with a mean age of 60.6 years (standard deviation, ±3.6 years). MAIN OUTCOME MEASURES: Effects on CLS density and gene expression in abdominal subcutaneous adipose tissue, cardiometabolic risk factors, white blood count, circulating metabolites, and oxidative stress (urinary isoprostane-M) were measured. RESULTS: Obese subjects lost approximately 10% body weight over a mean of 46 days. CLS density increased in subcutaneous adipose tissue without an associated increase in proinflammatory gene expression. Weight loss was accompanied by decreased fasting blood levels of high-sensitivity C-reactive protein, glucose, lactate, and kynurenine, and increased circulating levels of free fatty acids, glycerol, ß-hydroxybutyrate, and 25 hydroxyvitamin D. Levels of urinary isoprostane-M declined. CONCLUSION: Rapid weight loss stimulated lipolysis and an increase in CLS density in subcutaneous adipose tissue in association with changes in levels of circulating metabolites, and improved systemic biomarkers of inflammation and insulin resistance. The observed change in levels of metabolites (i.e., lactate, ß-hydroxybutyrate, 25 hydroxyvitamin D) may contribute to the anti-inflammatory effect of rapid weight loss.

Noninvasive Detection of Inflammatory Changes in White Adipose Tissue by Label-Free Raman Spectroscopy.

White adipose tissue inflammation (WATi) has been linked to the pathogenesis of obesity-related diseases, including type 2 diabetes, cardiovascular disease, and cancer. In addition to the obese, a substantial number of normal and overweight individuals harbor WATi, putting them at increased risk for disease. We report the first technique that has the potential to detect WATi noninvasively. Here, we used Raman spectroscopy to detect WATi with excellent accuracy in both murine and human tissues. This is a potentially significant advance over current histopathological techniques for the detection of WATi, which rely on tissue excision and, therefore, are not practical for assessing disease risk in the absence of other identifying factors. Importantly, we show that noninvasive Raman spectroscopy can diagnose WATi in mice. Taken together, these results demonstrate the potential of Raman spectroscopy to provide objective risk assessment for future cardiometabolic complications in both normal weight and overweight/obese individuals.

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies.

Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment.

Mechanisms of obesity-induced gastrointestinal neoplasia.

Obesity is among the fastest growing diseases worldwide; treatment is inadequate, and associated disorders, including gastrointestinal cancers, have high morbidity and mortality. An increased understanding of the mechanisms of obesity-induced carcinogenesis is required to develop methods to prevent or treat these cancers. In this report, we review the mechanisms of obesity-associated colorectal, esophageal, gastric, and pancreatic cancers and potential treatment strategies.

Tracking cellular metabolomics in lipoapoptosis- and steatosis-developing liver cells.

Palmitate (PA) is known to induce reactive oxygen species (ROS) formation and apoptosis in liver cells, whereas concurrent treatment of oleate (OA) with PA predominately induces steatosis without ROS in liver cells. We previously reported that PA treatment induces the decoupling of glycolysis and tricarboxylic acid cycle (TCA cycle) fluxes, but OA co-treatment restored most metabolic fluxes to their control levels. However, the mechanisms by which metabolites are linked to metabolic fluxes and subsequent lipoapoptotic or steatotic phenotypes remain unclear. To determine the link, we used GC-MS-based polar and non-polar metabolic profiling in lipoapoptosis- or steatosis-developing H4IIEC3 hepatoma cells, to examine the metabolome at different time points after treatment with either PA alone (PA cells) or both PA and OA (PA/OA cells). Metabolic profiles revealed various changes in metabolite levels for TCA cycle intermediates, pentose phosphate pathway (PPP) intermediates, and energy storage metabolites between PA and PA/OA cells. For example, adenosine was markedly increased only in PA cells, whereas gluconate was increased in PA/OA cells. To assess the interaction among these metabolites, the metabolite-to-metabolite correlations were calculated and correlation networks were visualized. These correlation networks demonstrate that a dissociation among PPP metabolites was introduced in PA-treated cells, and this dissociation was restored in PA/OA-treated cells. Thus, our data suggest that abnormal PPP fluxes, in addition to increased adenosine levels, might be related to the decoupling of glycolysis and the resulting lipoapoptotic phenotype.

The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling.

Phosphoinositide 3-kinase (PI3K) plays a critical role in tumorigenesis, and the PI3K p85 regulatory subunit exerts both positive and negative effects on signaling. Expression of Pik3r1, the gene encoding p85, is decreased in human prostate, lung, ovarian, bladder, and liver cancers, consistent with the possibility that p85 has tumor suppressor properties. We tested this hypothesis by studying mice with a liver-specific deletion of the Pik3r1 gene. These mice exhibited enhanced insulin and growth factor signaling and progressive changes in hepatic pathology, leading to the development of aggressive hepatocellular carcinomas with pulmonary metastases. Liver tumors that arose exhibited markedly elevated levels of phosphatidylinositol (3,4,5)-trisphosphate, along with Akt activation and decreased PTEN expression, at both the mRNA and protein levels. Together, these results substantiate the concept that the p85 subunit of PI3K has a tumor-suppressive role in the liver and possibly other tissues.

Effect of anaplerotic fluxes and amino acid availability on hepatic lipoapoptosis.

To identify metabolic pathways involved in hepatic lipoapoptosis, metabolic flux analysis using [U-(13)C(5)]glutamine as an isotopic tracer was applied to quantify phenotypic changes in H4IIEC3 hepatoma cells treated with either palmitate alone (PA-cells) or both palmitate and oleate in combination (PA/OA-cells). Our results indicate that palmitate inhibited glycolysis and lactate dehydrogenase fluxes while activating citric acid cycle (CAC) flux and glutamine uptake. This decoupling of glycolysis and CAC fluxes occurred during the period following palmitate exposure but preceding the onset of apoptosis. Oleate co-treatment restored most fluxes to their control levels, resulting in steatotic lipid accumulation while preventing apoptosis. In addition, palmitate strongly increased the cytosolic NAD(+)/NADH ratio, whereas oleate co-treatment had the opposite effect on cellular redox. We next examined the influence of amino acids on these free fatty acid-induced phenotypic changes. Increased medium amino acids enhanced reactive oxygen species (ROS) generation and apoptosis in PA-cells but not in PA/OA-cells. Overloading the medium with non-essential amino acids induced apoptosis, but essential amino acid overloading partially ameliorated apoptosis. Glutamate was the most effective single amino acid in promoting ROS. Amino acid overloading also increased cellular palmitoyl-ceramide; however, ceramide synthesis inhibitors had no effect on measurable indicators of apoptosis. Our results indicate that free fatty acid-induced ROS generation and apoptosis are accompanied by the decoupling of glycolysis and CAC fluxes leading to abnormal cytosolic redox states. Amino acids play a modulatory role in these processes via a mechanism that does not involve ceramide accumulation.