Publications by authors named "Steven R Smith"

246 Publications

Twenty-four hour assessments of substrate oxidation reveal differences in metabolic flexibility in type 2 diabetes that are improved with aerobic training.

Diabetologia 2021 Oct 17;64(10):2322-2333. Epub 2021 Aug 17.

Translational Research Institute, AdventHealth, Orlando, FL, USA.

Aims/hypothesis: The aim of this study was to assess metabolic flexibility (MetFlex) in participants with type 2 diabetes within the physiologically relevant conditions of sleeping, the post-absorptive (fasting) state and during meals using 24 h whole-room indirect calorimetry (WRIC) and to determine the impact of aerobic training on these novel features of MetFlex.

Methods: Normal-weight, active healthy individuals (active; n = 9), obese individuals without type 2 diabetes (ND; n = 9) and obese individuals with type 2 diabetes (n = 23) completed baseline metabolic assessments. The type 2 diabetes group underwent a 10 week supervised aerobic training intervention and repeated the metabolic assessments. MetFlex was assessed by indirect calorimetry in response to insulin infusion and during a 24 h period in a whole-room indirect calorimeter. Indices of MetFlex evaluated by WRIC included mean RQ and RQ kinetic responses after ingesting a standard high-carbohydrate breakfast (RQ) and sleep RQ (RQ). Muscle mitochondrial energetics were assessed in the vastus lateralis muscle in vivo and ex vivo using P-magnetic resonance spectroscopy and high-resolution respirometry, respectively.

Results: The three groups had significantly different RQ values (active 0.823 ± 0.04, ND 0.860 ± 0.01, type 2 diabetes 0.842 ± 0.03; p < 0.05). The active group had significantly faster RQ and more stable RQ responses than the ND and type 2 diabetes groups, as demonstrated by steeper and flatter slopes, respectively. Following the training intervention, the type 2 diabetes group displayed significantly increased RQ slope. Several indices of RQ kinetics had significant associations with in vivo and ex vivo muscle mitochondrial capacities.

Conclusions/interpretation: Twenty-four hour WRIC revealed that physiological RQ responses exemplify differences in MetFlex across a spectrum of metabolic health and correlated with skeletal muscle mitochondrial energetics. Defects in certain features of MetFlex were improved with aerobic training, emphasising the need to assess multiple aspects of MetFlex and disentangle insulin resistance from MetFlex in type 2 diabetes.

Trial Registration: ClinicalTrials.gov NCT01911104.

Funding: This study was funded by the ADA (grant no. 7-13-JF-53).
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http://dx.doi.org/10.1007/s00125-021-05535-yDOI Listing
October 2021

DNA Methylation as a Marker of Body Shape in Premenopausal Women.

Front Genet 2021 29;12:709342. Epub 2021 Jul 29.

Translational Research Institute for Metabolism and Diabetes, AdventHealth, Orlando, FL, United States.

Preferential accumulation of fat in the gluteo-femoral (GF) depot (pear shape) rather than in the abdominal (A) depot (apple shape), protects against the development of metabolic diseases but the underlying molecular mechanism is still unknown. Recent data, including our work, suggest that differential epigenetic marking is associated with regulation of genes attributed to distinct fat distribution. Here, we aimed to compare the genomic DNA methylation signatures between apple and pear-shaped premenopausal women. To investigate the contribution of upper and lower body fat, we used paired samples of A-FAT and GF-FAT, analyzed on the BeadChip Methylation Array and quantified the differentially methylated sites between the 2 groups of women. We found unique DNA methylation patterns within both fat depots that are significantly different depending on the body fat distribution. Around 60% of the body shape specific DNA methylation sites identified in adipose tissue are maintained in cultured preadipocytes. As it has been reported before in other cell types, we found only a hand full of genes showing coordinated differential methylation and expression levels. Finally, we determined that more than 50% of the body shape specific DNA methylation sites could also be detected in whole blood derived DNA. These data reveal a strong DNA methylation program associated with adipose tissue distribution with the possibility that a simple blood test could be used as a predictive diagnostic indicator of young women who are at increased risk for progressing to the apple body shape with a higher risk of developing obesity related complications. https://clinicaltrials.gov/ct2/show/NCT02728635 and https://clinicaltrials.gov/ct2/show/NCT02226640, identifiers NCT02728635 and NCT02226640.
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http://dx.doi.org/10.3389/fgene.2021.709342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358448PMC
July 2021

Reliability of measurements of energy expenditure and substrate oxidation using whole-room indirect calorimetry.

Obesity (Silver Spring) 2021 Sep 6;29(9):1508-1515. Epub 2021 Aug 6.

Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA.

Objective: This analysis aimed to measure the intraparticipant reliability-the intraclass correlation coefficient-of all the components of daily energy expenditure (EE) (24-hour EE, sleep EE, resting EE, basal EE, and thermic effect of food) over a period of 3 consecutive days in 35 study participants.

Methods: The components of daily EE and substrate use (respiratory exchange ratio) were measured over 3 consecutive days before and after a 3-week 1,000-kcal/d caloric restriction/weight-loss intervention.

Results: There was a high degree of reliability for sleep EE (96.8%), 24-hour EE (97.8%), basal EE (90.6%), and resting EE (93.2%) during the run-in period. The intraclass correlation coefficient for the follow-up period after weight loss (3.67 ± 1.10 kg) remained high for sleep EE (95.6%), 24-hour EE (100%), basal EE (96.1%), and resting EE (92.5%). The minimal detectable differences in EE were reduced by 30% for both 24-hour EE and sleep EE when comparing 2 days versus 1 day spent in the whole-room indirect calorimeter.

Conclusions: The reliability of the daily components of EE is very high both prior to and after a weight-loss intervention. We here provide instrumental data for investigators to adequately power studies investigating energy metabolism using whole-room indirect calorimetry.
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http://dx.doi.org/10.1002/oby.23226DOI Listing
September 2021

A Metabolomic Signature of Glucagon Action in Healthy Individuals With Overweight/Obesity.

J Endocr Soc 2021 Sep 25;5(9):bvab118. Epub 2021 Jun 25.

Translational Research Institute, AdventHealth, Orlando, FL 32804, USA.

Context: Glucagon is produced and released from the pancreatic alpha-cell to regulate glucose levels during periods of fasting. The main target for glucagon action is the liver, where it activates gluconeogenesis and glycogen breakdown; however, glucagon is postulated to have other roles within the body.

Objective: We sought to identify the circulating metabolites that would serve as markers of glucagon action in humans.

Methods: In this study (NCT03139305), we performed a continuous 72-hour glucagon infusion in healthy individuals with overweight/obesity. Participants were randomized to receive glucagon 12.5 ng/kg/min (GCG 12.5), glucagon 25 ng/kg/min (GCG 25), or a placebo control. A comprehensive metabolomics analysis was then performed from plasma isolated at several time points during the infusion to identify markers of glucagon activity.

Results: Glucagon (GCG 12.5 and GCG 25) resulted in significant changes in the plasma metabolome as soon as 4 hours following infusion. Pathways involved in amino acid metabolism were among the most affected. Rapid and sustained reduction of a broad panel of amino acids was observed. Additionally, time-dependent changes in free fatty acids and diacylglycerol and triglyceride species were observed.

Conclusion: These results define a distinct signature of glucagon action that is broader than the known changes in glucose levels. In particular, the robust changes in amino acid levels may prove useful to monitor changes induced by glucagon in the context of additional glucagon-like peptide-1 or gastric inhibitory polypeptide treatment, as these agents also elicit changes in glucose levels.
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http://dx.doi.org/10.1210/jendso/bvab118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317630PMC
September 2021

Developing a model for estimating the activity of colonic microbes after intestinal surgeries.

PLoS One 2021 28;16(7):e0253542. Epub 2021 Jul 28.

Biodesign Center for Health Through Microbiomes, Arizona State University, Tempe, AZ, United States of America.

Background: The large intestine provides a compensatory role in energy recovery when surgical interventions such as extensive small intestinal resections or bypass operations lower the efficiency of nutrient absorption in the upper gastrointestinal (GI) tract. While microorganisms in the colon are known to play vital roles in recovering energy, their contributions remain to be qualified and quantified in the small intestine resection.

Objective: We develop a mathematical model that links nutrient absorption in the upper and lower GI tract in two steps.

Methods: First, we describe the effects of small intestine resection on the ileocecal output (ICO), which enters the colon and provides food for microbes. Second, we describe energy recovered by the colon's microorganisms via short-chain fatty acid (SCFA) production. We obtain model parameters by performing a least-squares regression analysis on clinical data for subjects with normal physiology and those who had undergone small intestine resection.

Results: For subjects with their intestines intact, our model provided a metabolizable energy value that aligns well with the traditional Atwater coefficients. With removal of the small intestine, physiological absorption became less efficient, and the metabolizable energy decreased. In parallel, the inefficiencies in physiological absorption by the small intestine are partly compensated by production of short-chain fatty acids (SCFA) from proteins and carbohydrates by microorganisms in the colon. The colon recovered more than half of the gross energy intake when the entire small intestine was removed. Meanwhile, the quality of energy absorbed changed, because microbe-derived SCFAs, not the original components of food, become the dominant form of absorbed energy.

Conclusion: The mathematical model developed here provides an important framework for describing the effect of clinical interventions on the colon's microorganisms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253542PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318292PMC
July 2021

Energy intake as a short-term biomarker for weight loss in adults with obesity receiving liraglutide: A randomized trial.

Obes Sci Pract 2021 Jun 9;7(3):281-290. Epub 2021 Mar 9.

AdventHealth Translational Research Institute Orlando Florida USA.

Background And Objective: Obesity is a chronic disease associated with many serious comorbidities. Pharmacologic therapies are approved for the treatment of obesity; however, short-term biomarkers to predict weight loss are not well understood. This study aimed to determine the ability of single-meal energy intake (EI) to predict weight loss in participants with obesity treated with liraglutide.

Methods: In this randomized, double-blind, placebo-controlled study, participants received subcutaneous liraglutide (titrated to 3.0 mg/day) or placebo once daily, with inpatient assessments at baseline and weeks 3 and 6. The primary endpoint was change from baseline (CFB) in EI during consecutive ad libitum lunch meals at weeks 3 and 6. Secondary endpoints included CFB in 24- and 48-h EI, weight, appetite scores, and gastric emptying measures.

Results: Sixty-one participants were randomized ( = 32, liraglutide;  = 29, placebo). The least squares mean (LSM) difference (95% CI; -value) in CFB in EI during ad libitum lunch meals between the liraglutide and placebo groups was -236 (-322, -149;  < 0.0001) kcal at week 3 and -244 (-339, -148,  < 0.0001) kcal at week 6. The liraglutide group experienced significant weight loss at weeks 3 and 6, compared with placebo. Weight loss was significantly correlated with EI, but not with appetite score or gastric emptying.

Conclusions: EI during a single meal is a robust clinical predictor of weight changes in participants with obesity. Future clinical trials can utilize EI at a single meal as a predictor of weight loss.
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http://dx.doi.org/10.1002/osp4.486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170575PMC
June 2021

Prolonged Glucagon Infusion Does Not Affect Energy Expenditure in Individuals with Overweight/Obesity: A Randomized Trial.

Obesity (Silver Spring) 2021 06;29(6):1003-1013

Translational Research Institute, AdventHealth, Orlando, Florida, USA.

Objective: The aim of this study was to determine the effects of prolonged (72 hours) glucagon administration at a low dose (LD) (12.5 ng/kg/min) and high dose (HD) (25 ng/kg/min) on energy expenditure (EE) in healthy individuals with overweight or obesity.

Methods: Thirty-one healthy participants with overweight or obesity (BMI of 27-45 kg/m , 26-55 years old, 23 females) were randomized into LD, HD, or placebo groups and underwent 72-hour intravenous infusion of glucagon. Whole-room calorimetry was used to assess EE and substrate use during five overnight stays (2 days at baseline, 3 days of infusion) and during two 24-hour stays (baseline vs. day 3). Blood was sampled at regular intervals throughout the inpatient stay and analyzed for glucagon and biomarkers of metabolism.

Results: HD infusion elevated plasma glucagon levels compared with the placebo and LD infusion (P < 0.001). Sleeping, basal, and 24-hour EE was not significantly different among groups at any time point. Those receiving HD had significantly higher basal fat oxidation (Fat Ox) at days 2 and 3 than those receiving the placebo (P < 0.05); however, no differences in 24-hour Fat Ox were observed among groups (baseline vs. day 3).

Conclusions: An HD plasma glucagon infusion over 72 hours does not increase any aspects of EE in healthy individuals with overweight or obesity.
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http://dx.doi.org/10.1002/oby.23141DOI Listing
June 2021

Metabolic adaptation characterizes short-term resistance to weight loss induced by a low-calorie diet in overweight/obese individuals.

Am J Clin Nutr 2021 07;114(1):267-280

Translational Research Institute, AdventHealth, Orlando, FL, USA.

Background: Low-calorie diet (LCD)-induced weight loss demonstrates response heterogeneity. Physiologically, a decrease in energy expenditure lower than what is predicted based on body composition (metabolic adaptation) and/or an impaired capacity to increase fat oxidation may hinder weight loss. Understanding the metabolic components that characterize weight loss success is important for optimizing weight loss strategies.

Objectives: We tested the hypothesis that overweight/obese individuals who had lower than expected weight loss in response to a 28-d LCD would be characterized by 1) impaired fat oxidation and 2) whole-body metabolic adaptation. We also characterized the molecular mechanisms associated with weight loss success/failure.

Methods: This was a retrospective comparison of participants who met their predicted weight loss targets [overweight/obese diet sensitive (ODS), n = 23, females = 21, males = 2] and those that did not [overweight/obese diet resistant (ODR), n = 14, females = 12, males = 2] after a 28-d LCD (900-1000 kcal/d). We used whole-body (energy expenditure and fat oxidation) and tissue-specific measurements (metabolic proteins in skeletal muscle, gene expression in adipose tissue, and metabolites in serum) to detect metabolic properties and biomarkers associated with weight loss success.

Results: The ODR group had greater mean ± SD metabolic adaptation (-175 ± 149 kcal/d; +119%) than the ODS group (-80 ± 108 kcal/d) after the LCD (P = 0.030). Mean ± SD fat oxidation increased similarly for both groups from baseline (0.0701 ± 0.0206 g/min) to day 28 (0.0869 ± 0.0269 g/min; P < 0.001). A principal component analysis factor comprised of serum 3-hydroxybutyric acid, citrate, leucine/isoleucine, acetyl-carnitine, and 3-hydroxylbutyrlcarnitine was associated with weight loss success at day 28 (std. β = 0.674, R2 = 0.479, P < 0.001).

Conclusions: Individuals who achieved predicted weight loss targets after a 28-d LCD were characterized by reduced metabolic adaptation. Accumulation of metabolites associated with acetyl-CoA excess and enhanced ketogenesis was identified in the ODS group.This trial was registered at clinicaltrials.gov as NCT01616082.
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http://dx.doi.org/10.1093/ajcn/nqab027DOI Listing
July 2021

Physiology of Energy Expenditure in the Weight-Reduced State.

Obesity (Silver Spring) 2021 04;29 Suppl 1:S31-S38

Naomi Berrie Diabetes Center, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA.

Although many individuals achieve weight loss of 10% or more, the ability to maintain a reduced body mass over months and years is much rarer. Unfortunately, our understanding of the adverse consequences of having overweight and obesity argues that long-term maintenance of a reduced weight provides the greatest health benefit. However, to achieve long-term weight reduction requires overcoming neuroendocrine systems that favor restoration of one's initial weight. Identifying and characterizing the components of these systems will be important if we are to develop therapies and strategies to reduce the rates of obesity and its complications in our modern society. During this session, Eric Ravussin and Steven R. Smith, respectively, discussed the physiology of the weight-reduced state that favors weight regain and a molecular component that contributes to this response.
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http://dx.doi.org/10.1002/oby.23095DOI Listing
April 2021

Effect of Overeating Dietary Protein at Different Levels on Circulating Lipids and Liver Lipid: The PROOF Study.

Nutrients 2020 Dec 11;12(12). Epub 2020 Dec 11.

Pennington Biomedical Research Center-LSU, Baton Rouge, LA 70808, USA.

Background: During overeating, a low protein diet slowed the rate of weight gain and increased the energy cost of the added weight, suggesting that low protein diets reduced energy efficiency. The Protein Overfeeding (PROOF) study explored the metabolic changes to low and high protein diets, and this sub-study examined the changes in body composition and blood lipids when eating high and low protein diets during overeating.

Methods: Twenty-three healthy volunteers (M = 14; F = 9) participated in an 8-week, parallel arm study where they were overfed by ~40% with diets containing 5% (LPD = low protein diet), 15% (NPD = normal protein diet), or 25% (HPD = high protein diet) protein. Dual energy X-ray absorptiometry (DXA) and computer tomography (CT) were used to quantify whole body and abdominal fat and intrahepatic lipid, respectively. Metabolites were measured by standard methods.

Results: Protein intake and fat intake were inversely related since carbohydrate intake was fixed. Although overeating the LPD diet was associated with a significant increase in high density lipoprotein (HDL)-cholesterol ( < 0.001) and free fatty acids ( = 0.034), and a significant decrease in fat free mass ( < 0.0001) and liver density ( = 0.038), statistical models showed that dietary protein was the main contributor to changes in fat free mass ( = 0.0040), whereas dietary fat was the major predictor of changes in HDL-cholesterol ( = 0.014), free fatty acids ( = 0.0016), and liver fat ( = 0.0007).

Conclusions: During 8 weeks of overeating, the level of dietary protein intake was positively related to the change in fat free mass, but not to the change in HDL-cholesterol, free fatty acids, and liver fat which were, in contrast, related to the intake of dietary fat.
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http://dx.doi.org/10.3390/nu12123801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763540PMC
December 2020

Chemical Oxygen Demand Can Be Converted to Gross Energy for Food Items Using a Linear Regression Model.

J Nutr 2021 02;151(2):445-453

Biodesign Swette Center for Environmental Biotechnology, Arizona State University, Tempe, AZ, USA.

Background: Human and microbial metabolism are distinct disciplines. Terminology, metrics, and methodologies have been developed separately. Therefore, combining the 2 fields to study energetic processes simultaneously is difficult.

Objectives: When developing a mechanistic framework describing gut microbiome and human metabolism interactions, energy values of food and digestive materials that use consistent and compatible metrics are required. As an initial step toward this goal, we developed and validated a model to convert between chemical oxygen demand (COD) and gross energy (${E_g}$) for >100 food items and ingredients.

Methods: We developed linear regression models to relate (and be able to convert between) theoretical gross energy (${E_g}^{\prime}$) and chemical oxygen demand (COD'); the latter is a measure of electron equivalents in the food's carbon. We developed an overall regression model for the food items as a whole and separate regression models for the carbohydrate, protein, and fat components. The models were validated using a sample set of computed ${E_g}^{\prime}$ and COD' values, an experimental sample set using measured ${E_g}$ and COD values, and robust statistical methods.

Results: The overall linear regression model and the carbohydrate, protein, and fat regression models accurately converted between COD and ${E_g}$, and the component models had smaller error. Because the ratios of COD per gram dry weight were greatest for fats and smallest for carbohydrates, foods with a high fat content also had higher ${E_g}$ values in terms of kcal · g dry weight-1.

Conclusion: Our models make it possible to analyze human and microbial energetic processes in concert using a single unit of measure, which fills an important need in the food-nutrition-metabolism-microbiome field. In addition, measuring COD and using the regressions to calculate ${E_g}$ can be used instead of measuring ${E_g}$ directly using bomb calorimetry, which saves time and money.
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http://dx.doi.org/10.1093/jn/nxaa321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850027PMC
February 2021

Supreme Court 2019-2020: Insanity, Discrimination, and DACA-And a Pandemic.

Authors:
Steven R Smith

J Health Serv Psychol 2020 Oct 29:1-19. Epub 2020 Oct 29.

San Diego, CA USA.

The 2019-2020 Supreme Court session was an extraordinary session. One major ruling involved insanity defense and whether the two prongs of cognitive capacity and moral capacity were required. Sexual identity was ruled to be covered by the Civil Rights Act in relation to employment. Unanimous criminal jury decisions were ruled a required condition for conviction. The rescindment of DACA was overturned on procedural grounds. Other decisions related to conditions of abortion, habitual residence in international custody cases, police immunity from civil liability, guns, HIV, and capital punishment. Thirty-five percent of cases were unanimous (down from the recent average), and 22% were decided by a 5-4 vote (slightly above the recent average).
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http://dx.doi.org/10.1007/s42843-020-00021-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595055PMC
October 2020

A Novel Endocrine Role for the BAT-Released Lipokine 12,13-diHOME to Mediate Cardiac Function.

Circulation 2021 Jan 27;143(2):145-159. Epub 2020 Oct 27.

Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (K.M.P., V.K.S., K.R.W., E.A., L.A.B., P.V., R.S.D., D.H.-S., P.J.A., A.C.L., E.D.L., S.V.R., L.E.W., D.G.P., M.T.Z., K.I.S.).

Background: Brown adipose tissue (BAT) is an important tissue for thermogenesis, making it a potential target to decrease the risks of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified BAT as an endocrine organ. Although BAT has been implicated to be protective in cardiovascular disease, to this point there are no studies that identify a direct role for BAT to mediate cardiac function.

Methods: To determine the role of BAT on cardiac function, we utilized a model of BAT transplantation. We then performed lipidomics and identified an increase in the lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). We utilized a mouse model with sustained overexpression of 12,13-diHOME and investigated the role of 12,13-diHOME in a nitric oxide synthase type 1 deficient (NOS1) mouse and in isolated cardiomyocytes to determine effects on function and respiration. We also investigated 12,13-diHOME in a cohort of human patients with heart disease.

Results: Here, we determined that transplantation of BAT (+BAT) improves cardiac function via the release of the lipokine 12,13-diHOME. Sustained overexpression of 12,13-diHOME using tissue nanotransfection negated the deleterious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13-diHOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13-diHOME increased mitochondrial respiration. The effects of 12,13-diHOME were absent in mice and cardiomyocytes. We also provide the first evidence that 12,13-diHOME is decreased in human patients with heart disease.

Conclusions: Our results identify an endocrine role for BAT to enhance cardiac function that is mediated by regulation of calcium cycling via 12,13-diHOME and NOS1.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856257PMC
January 2021

Integrative and quantitative bioenergetics: Design of a study to assess the impact of the gut microbiome on host energy balance.

Contemp Clin Trials Commun 2020 Sep 19;19:100646. Epub 2020 Aug 19.

AdventHealth, Translational Research Institute, Orlando, FL, USA.

The literature is replete with clinical studies that characterize the structure, diversity, and function of the gut microbiome and correlate the results to different disease states, including obesity. Whether the microbiome has a direct impact on obesity has not been established. To address this gap, we asked whether the gut microbiome and its bioenergetics quantitatively change host energy balance. This paper describes the design of a randomized crossover clinical trial that combines outpatient feeding with precisely controlled metabolic phenotyping in an inpatient metabolic ward. The target population was healthy, weight-stable individuals, age 18-45 and with a body mass index ≤30 kg/m. Our primary objective was to determine within-participant differences in energy balance after consuming a control Western Diet versus a Microbiome Enhancer Diet intervention specifically designed to optimize the gut microbiome for positive impacts on host energy balance. We assessed the complete energy-balance equation via whole-room calorimetry, quantified energy intake, fecal energy losses, and methane production. We implemented conditions of tight weight stability and balance between metabolizable energy intake and predicted energy expenditure. We explored key factors that modulate the balance between host and microbial nutrient accessibility by measuring enteroendocrine hormone profiles, appetite/satiety, gut transit and gastric emptying. By integrating these clinical measurements with future bioreactor experiments, gut microbial ecology analysis, and mathematical modeling, our goal is to describe initial cause-and-effect mechanisms of gut microbiome metabolism on host energy balance. Our innovative methods will enable subsequent studies on the interacting roles of diet, the gut microbiome, and human physiology.

Clinicaltrialsgov Identifier: NCT02939703. The present study reference can be found here: https://clinicaltrials.gov/ct2/show/NCT02939703.
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http://dx.doi.org/10.1016/j.conctc.2020.100646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451766PMC
September 2020

An improvement in skeletal muscle mitochondrial capacity with short-term aerobic training is associated with changes in Tribbles 1 expression.

Physiol Rep 2020 06;8(12):e14416

Translational Research Institute, AdventHealth, Orlando, FL, USA.

Exercise training and physical activity are known to be associated with high mitochondrial content and oxidative capacity in skeletal muscle. Metabolic diseases including obesity and insulin resistance are associated with low mitochondrial capacity in skeletal muscle. Certain transcriptional factors such as PGC-1α are known to mediate the exercise response; however, the precise molecular mechanisms involved in the adaptation to exercise are not completely understood. We performed multiple measurements of mitochondrial capacity both in vivo and ex vivo in lean or overweight individuals before and after an 18-day aerobic exercise training regimen. These results were compared to lean, active individuals. Aerobic training in these individuals resulted in a marked increase in mitochondrial oxidative respiratory capacity without an appreciable increase in mitochondrial content. These adaptations were associated with robust transcriptome changes. This work also identifies the Tribbles pseudokinase 1, TRIB1, as a potential mediator of the exercise response in human skeletal muscle.
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http://dx.doi.org/10.14814/phy2.14416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305239PMC
June 2020

Fat Distribution in Women Is Associated With Depot-Specific Transcriptomic Signatures and Chromatin Structure.

J Endocr Soc 2020 Jun 8;4(6):bvaa042. Epub 2020 Apr 8.

Translational Research Institute for Metabolism and Diabetes, AdventHealth, Orlando, FL, USA.

Background: Preferential accumulation of fat in the upper body (apple shape) is associated with higher risk of developing metabolic syndrome relative to lower body fat (pear shape). We previously discovered that chromatin openness partially defined the transcriptome of preadipocytes isolated from abdominal and gluteofemoral fat. However, the molecular mechanisms underlying interindividual variation in body shape are unknown.

Methods: Adipocyte fraction was isolated from abdominal and gluteofemoral fat biopsies of premenopausal women (age and body mass index matched) segregated initially only by their waist-to-hip ratio. We evaluated transcriptomic and chromatin accessibility using RNA sequencing and assay for transposase-accessible chromatin using sequencing (ATAC-seq) along with key clinical parameters.

Results: Our data showed that higher lower body fat mass was associated with better lipid profile and free fatty acid decrease after glucose administration. Lipid and glucose metabolic pathways genes were expressed at higher levels in gluteofemoral adipocyte fraction in pears, whereas genes associated with inflammation were higher both in abdominal and gluteofemoral apple adipocyte fraction. Gluteofemoral adipocyte chromatin from pear-shaped women contained a significantly higher number of differentially open ATAC-seq peaks relative to chromatin from the apple-shaped gluteofemoral adipocytes. In contrast, abdominal adipocyte chromatin openness showed few differences between apple- and pear-shaped women. We revealed a correlation between gene transcription and open chromatin at the proximity of the transcriptional start site of some of the differentially expressed genes.

Conclusions: Integration of data from all 3 approaches suggests that chromatin openness partially governs the transcriptome of gluteofemoral adipocytes and may be involved in the early metabolic syndrome predisposition associated with body shape.
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http://dx.doi.org/10.1210/jendso/bvaa042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261146PMC
June 2020

Social tipping intervention strategies for rapid decarbonization need to consider how change happens.

Proc Natl Acad Sci U S A 2020 05 23;117(20):10629-10630. Epub 2020 Apr 23.

Lancaster Environment Centre, University of Lancaster, Lancaster LA1 4YQ, United Kingdom.

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http://dx.doi.org/10.1073/pnas.2002331117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245064PMC
May 2020

Plasma Myokine Concentrations After Acute Exercise in Non-obese and Obese Sedentary Women.

Front Physiol 2020 18;11:18. Epub 2020 Feb 18.

Institut du Savoir Montfort, Ottawa, ON, Canada.

Exercise and physical activity levels influence myokine release from skeletal muscle and contribute to circulating concentrations. Indeed, many myokines, including interleukin (IL)-6, IL-15, secreted protein acidic rich in cysteine (SPARC), and fibroblast growth factor (FGF) 21 are higher in the circulation after an exercise bout. Since these peptides modulate muscle metabolism and can also be targeted toward other tissues to induce adaptations to energy demand, they are of great interest regarding metabolic diseases. Therefore, we set out to compare, in six women with obesity (BMI ≥30 kg/m) and five healthy women (BMI 22-29.9 kg/m), the effect of an acute bout of moderate-intensity, continuous cycling exercise (60 min, 60% VOpeak) on the release of myokines (IL-6, IL-8, IL-10, IL-13, IL-15, SPARC, and FGF21) in plasma for a 24-h time course. We found that plasma IL-8 and SPARC levels were reduced in the group of women with obesity, whereas plasma IL-13 concentrations were elevated in comparison to non-obese women both before and after the exercise bout. We also found that plasma FGF21 concentration during the 24 h following the bout of exercise was regulated differently in the non-obese in comparison to obese women. Plasma concentrations of FGF21, IL-6, IL-8, IL-15, and IL-18 were regulated by acute exercise. Our results confirm the results of others concerning exercise regulation of circulating myokines while providing insight into the time course of myokine release in circulation after an acute exercise bout and the differences in circulating myokines after exercise in women with or without obesity.
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http://dx.doi.org/10.3389/fphys.2020.00018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040180PMC
February 2020

Reply to DS Ludwig et al.

Am J Clin Nutr 2019 11;110(5):1255-1256

Pennington Biomedical Research Center, Orlando, FL.

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http://dx.doi.org/10.1093/ajcn/nqz157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307317PMC
November 2019

Endurance training remodels skeletal muscle phospholipid composition and increases intrinsic mitochondrial respiration in men with Type 2 diabetes.

Physiol Genomics 2019 11 7;51(11):586-595. Epub 2019 Oct 7.

Translational Research Institute for Metabolism and Diabetes, Adventhealth, Orlando, Florida.

The effects of exercise training on the skeletal muscle (SKM) lipidome and mitochondrial function have not been thoroughly explored in individuals with Type 2 diabetes (T2D). We hypothesize that 10 wk of supervised endurance training improves SKM mitochondrial function and insulin sensitivity that are related to alterations in lipid signatures within SKM of T2D (males = 8). We employed integrated multi-omics data analyses including ex vivo lipidomics (MS/MS-shotgun) and transcriptomics (RNA-Seq). From biopsies of SKM, tissue and primary myotubes mitochondrial respiration were quantified by high-resolution respirometry. We also performed hyperinsulinemic-euglycemic clamps and blood draws before and after the training. The lipidomics analysis revealed that endurance training (>95% compliance) increased monolysocardiolipin by 68.2% ( ≤ 0.03), a putative marker of mitochondrial remodeling, and reduced total sphingomyelin by 44.8% ( ≤ 0.05) and phosphatidylserine by 39.7% ( ≤ 0.04) and tended to reduce ceramide lipid content by 19.8%. Endurance training also improved intrinsic mitochondrial respiration in SKM of T2D without alterations in mitochondrial DNA copy number or cardiolipin content. RNA-Seq revealed 71 transcripts in SKM of T2D that were differentially regulated. Insulin sensitivity was unaffected, and HbA1c levels moderately increased by 7.3% despite an improvement in cardiorespiratory fitness (V̇o) following the training intervention. In summary, endurance training improves intrinsic and cell-autonomous SKM mitochondrial function and modifies lipid composition in men with T2D independently of alterations in insulin sensitivity and glycemic control.
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http://dx.doi.org/10.1152/physiolgenomics.00014.2019DOI Listing
November 2019

Boosting NAD with a small molecule that activates NAMPT.

Nat Commun 2019 07 19;10(1):3241. Epub 2019 Jul 19.

Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.

Pharmacological strategies that boost intracellular NAD are highly coveted for their therapeutic potential. One approach is activation of nicotinamide phosphoribosyltransferase (NAMPT) to increase production of nicotinamide mononucleotide (NMN), the predominant NAD precursor in mammalian cells. A high-throughput screen for NAMPT activators and hit-to-lead campaign yielded SBI-797812, a compound that is structurally similar to active-site directed NAMPT inhibitors and blocks binding of these inhibitors to NAMPT. SBI-797812 shifts the NAMPT reaction equilibrium towards NMN formation, increases NAMPT affinity for ATP, stabilizes phosphorylated NAMPT at His247, promotes consumption of the pyrophosphate by-product, and blunts feedback inhibition by NAD. These effects of SBI-797812 turn NAMPT into a "super catalyst" that more efficiently generates NMN. Treatment of cultured cells with SBI-797812 increases intracellular NMN and NAD. Dosing of mice with SBI-797812 elevates liver NAD. Small molecule NAMPT activators such as SBI-797812 are a pioneering approach to raise intracellular NAD and realize its associated salutary effects.
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http://dx.doi.org/10.1038/s41467-019-11078-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642140PMC
July 2019

Metabolic adaptation is not observed after 8 weeks of overfeeding but energy expenditure variability is associated with weight recovery.

Am J Clin Nutr 2019 10;110(4):805-813

Clinical Science, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.

Background: A metabolic adaptation, defined as an increase in energy expenditure (EE) beyond what is expected with weight gain during overfeeding (OF), has been reported but also refuted. Much of the inconsistency stems from the difficulty in conducting large, well-controlled OF studies in humans.

Objectives: The primary aim of this study was to determine whether a metabolic adaptation to OF exists and if so, attenuates weight gain.

Methods: Thirty-five young adults consumed 40% above their baseline energy requirements for 8 wk, and sleeping metabolic rate (SMR) and 24-h sedentary energy expenditure (24h-EE) were measured before and after OF. Subjects were asked to return for a 6-mo post-OF follow-up visit to measure body weight, body composition, and physical activity.

Results: After adjusting for gains in fat-free mass and fat mass, SMR increased by 43 ± 123 kcal/d more than expected (P = 0.05) and 24h-EE by 23 ± 139 kcal/d (P = 0.34), indicating an overall lack of metabolic adaptation during OF despite a wide variability in the response. Among the 30 subjects who returned for the 6-mo follow-up visit, those who had a lower-than-predicted SMR (basal EE) retained more of the fat gained during OF. Likewise, subjects displaying a higher-than-predicted sedentary 24h-EE lost significantly more fat during the 6-mo follow-up.

Conclusions: Metabolic adaptation to OF was on average very small but variable between subjects, revealing "thrifty" or "spendthrift" metabolic phenotypes related to body weight loss 6 mo later. This trial was registered at clinicaltrials.gov as NCT01672632.
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http://dx.doi.org/10.1093/ajcn/nqz108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766445PMC
October 2019

Glucose and Lipid Homeostasis and Inflammation in Humans Following an Isocaloric Ketogenic Diet.

Obesity (Silver Spring) 2019 06 8;27(6):971-981. Epub 2019 May 8.

Departments of Pediatrics and Medicine, Division of Molecular Genetics, Columbia University Irving Medical Center, New York, New York, USA.

Objective: The objective of this study was to measure changes in glucose, lipid, and inflammation parameters after transitioning from a baseline diet (BD) to an isocaloric ketogenic diet (KD).

Methods: Glucose homeostasis, lipid homeostasis, and inflammation were studied in 17 men (BMI: 25-35 kg/m ) during 4 weeks of a BD (15% protein, 50% carbohydrate, 35% fat) followed by 4 weeks of an isocaloric KD (15% protein, 5% carbohydrate, 80% fat). Postprandial responses were assessed following mixed-meal tests matched to compositions of the BD (control meal [CM]) and KD (ketogenic meal).

Results: Fasting ketones, glycerol, free fatty acids, glucagon, adiponectin, gastric inhibitory peptide, total and low-density lipoprotein cholesterol, and C-reactive protein were significantly increased on the KD. Fasting insulin, C-peptides, triglycerides, and fibroblast growth factor 21 were significantly decreased. During the KD, the glucose area under the curve was significantly higher with both test meals, and the insulin area under the curve was significantly higher only for the CM. Analyses of glucose homeostasis suggested that the KD insulin sensitivity decreased during the CM but increased during the ketogenic meal. Insulin-mediated antilipolysis was decreased on the KD regardless of meal type.

Conclusions: Switching to the KD was associated with increased cholesterol and inflammatory markers, decreased triglycerides, and decreased insulin-mediated antilipolysis. Glucose homeostasis parameters were diet dependent and test meal dependent.
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http://dx.doi.org/10.1002/oby.22468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922028PMC
June 2019

Methodologic considerations for measuring energy expenditure differences between diets varying in carbohydrate using the doubly labeled water method.

Am J Clin Nutr 2019 05;109(5):1328-1334

Pennington Biomedical Research Center, Baton Rouge, LA.

Background: Low-carbohydrate diets have been reported to significantly increase human energy expenditure when measured using doubly labeled water (DLW) but not by respiratory chambers. Although DLW may reveal true physiological differences undetected by respiratory chambers, an alternative possibility is that the expenditure differences resulted from failure to correctly estimate the respiratory quotient (RQ) used in the DLW calculations.

Objective: To examine energy expenditure differences between isocaloric diets varying widely in carbohydrate and to quantitatively compare DLW data with respiratory chamber and body composition measurements within an energy balance framework.

Design: DLW measurements were obtained during the final 2 wk of month-long baseline (BD; 50% carbohydrate, 35% fat, 15% protein) and isocaloric ketogenic diets (KD; 5% carbohydrate, 80% fat, 15% protein) in 17 men with a BMI of 25-35 kg/m2. Subjects resided 2 d/wk in respiratory chambers to measure energy expenditure (EEchamber). DLW expenditure was calculated using chamber-determined RQ either unadjusted (EEDLW) or adjusted (EEDLWΔRQ) for net energy imbalance using diet-specific coefficients. Accelerometers measured physical activity. Body composition changes were measured by dual-energy X-ray absorptiometry (DXA) which were combined with energy intake measurements to calculate energy expenditure by balance (EEbal).

Results: After transitioning from BD to KD, neither EEchamber nor EEbal were significantly changed (∆EEchamber = 24 ± 30 kcal/d; P = 0.43 and ∆EEbal = -141 ± 118 kcal/d; P = 0.25). Similarly, physical activity (-5.1 ± 4.8%; P = 0.3) and exercise efficiency (-1.6 ± 2.4%; P = 0.52) were not significantly changed. However, EEDLW was 209 ± 83 kcal/d higher during the KD (P = 0.023) but was not significantly increased when adjusted for energy balance (EEDLWΔRQ = 139 ± 89 kcal/d; P = 0.14). After removing 2 outliers whose EEDLW were incompatible with other data, EEDLW was marginally increased during the KD by 126 ± 62 kcal/d (P = 0.063) and EEDLW∆RQ was only 46 ± 65 kcal/d higher (P = 0.49).

Conclusions: DLW calculations failing to account for diet-specific energy imbalance effects on RQ erroneously suggest that low-carbohydrate diets substantially increase energy expenditure. This trial was registered at clinicaltrials.gov as NCT01967563.
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http://dx.doi.org/10.1093/ajcn/nqy390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499509PMC
May 2019

GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.

Cell Metab 2019 03 10;29(3):707-718.e8. Epub 2019 Jan 10.

Department of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway.

GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.
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http://dx.doi.org/10.1016/j.cmet.2018.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408327PMC
March 2019

Lorcaserin and Renal Outcomes in Obese and Overweight Patients in the CAMELLIA-TIMI 61 Trial.

Circulation 2019 01;139(3):366-375

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (B.M.S., E.A.B., A.Q., S.A.M., K.I., M.P.B., C.T.R., M.S.S., S.D.W.).

Background: Obesity is thought to increase renal hyperfiltration, thereby increasing albuminuria and the progression of renal disease. The effect of pharmacologically mediated weight loss on renal outcomes is not well-described. Lorcaserin, a selective serotonin 2C receptor agonist that promotes appetite suppression, led to sustained weight loss without any increased risk for major adverse cardiovascular (CV) events in the CAMELLIA-TIMI 61 trial (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61).

Methods: CAMELLIA-TIMI 61 randomly assigned 12 000 overweight or obese patients with or at high risk for atherosclerotic CV disease to lorcaserin or placebo on a background of lifestyle modification. The primary renal outcome was a composite of new or worsening persistent micro- or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death.

Results: At baseline, 23.8% of patients had an estimated glomerular filtration rate (eGFR) <60 mL·min·1.73 m and 19.0% had albuminuria (urinary albumin:creatinine ratio ≥30 mg/g). Lorcaserin reduced the risk of the primary renal composite outcome (4.2% per year versus 4.9% per year; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79-0.96; P=0.0064). The benefit was consistent across subpopulations at increased baseline CV and renal risk. Lorcaserin improved both eGFR and urinary albumin:creatinune ratio within the first year after randomization. The effect of lorcaserin on weight, hemoglobin A1c, and systolic blood pressure was consistent regardless of baseline renal function. Likewise, there was no excess in cardiovascular events in patients assigned to lorcaserin in comparison with placebo, regardless of renal function. After adjustment for baseline characteristics, those with evidence of kidney disease were at increased risk of major CV events. Compared with patients with an eGFR ≥90 mL·min·1.73 m, those with an eGFR 60-90 and those <60 mL·min·1.73 m-2 had HRs of 1.25 (95% CI, 1.01, 1.56) and 1.51 (95% CI, 1.17, 1.95), respectively ( P for trend 0.0015). Likewise, compared with patients with no albuminuria (<30 mg/g), those microalbuminuria and those with macroalbuminuria had HRs of 1.46 (95% CI, 1.22, 1.74) and 2.10 (95% CI, 1.58, 2.80), respectively ( P for trend <0.0001).

Conclusions: Renal dysfunction was associated with increased CV risk in overweight and obese patients. When added to diet and lifestyle, lorcaserin reduced the rate of new-onset or progressive renal impairment in comparison with placebo.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02019264.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.038341DOI Listing
January 2019

Differential open chromatin profile and transcriptomic signature define depot-specific human subcutaneous preadipocytes: primary outcomes.

Clin Epigenetics 2018 11 26;10(1):148. Epub 2018 Nov 26.

Translational Research Institute for Metabolism and Diabetes, Florida Hospital, 301 E. Princeton Street, Orlando, FL, 32804, USA.

Background: Increased lower body fat is associated with reduced cardiometabolic risk. The molecular basis for depot-specific differences in gluteofemoral (GF) compared with abdominal (A) subcutaneous adipocyte function is poorly understood. In the current report, we used a combination of Assay for Transposase-Accessible Chromatin followed by sequencing (ATAC-seq), RNA-seq, and chromatin immunoprecipitation (ChIP)-qPCR analyses that provide evidence that depot-specific gene expression patterns are associated with differential epigenetic chromatin signatures.

Methods: Preadipocytes cultured from A and GF adipose tissue obtained from premenopausal apple-shaped women were used to perform transcriptome analysis by RNA-seq and assess accessible chromatin regions by ATAC-seq. We measured mRNA expression and performed ChIP-qPCR experiments for histone modifications of active (H3K4me3) and repressed chromatin (H3K27me3) regions respectively on the promoter regions of differentially expressed genes.

Results: RNA-seq experiments revealed an A-fat and GF-fat selective gene expression signature, with 126 genes upregulated in abdominal preadipocytes and 90 genes upregulated in GF cells. ATAC-seq identified almost 10-times more A-specific chromatin-accessible regions. Using a combined analysis of ATAC-seq and global gene expression data, we identified 74 of the 126 abdominal-specific genes (59%) with A-specific accessible chromatin sites within 200 kb of the transcription start site (TSS), including HOXA3, HOXA5, IL8, IL1b, and IL6. Interestingly, only 14 of the 90 GF-specific genes (15%) had GF-specific accessible chromatin sites within 200 kb of the corresponding TSS, including HOXC13 and HOTAIR, whereas 25 of them (28%) had abdominal-specific accessible chromatin sites. ChIP-qPCR experiments confirmed that the active H3K4me3 chromatin mark was significantly enriched at the promoter regions of HOXA5 and HOXA3 genes in abdominal preadipocytes, while H3K27me3 was less abundant relative to chromatin from GF. This is consistent with their A-fat specific gene expression pattern. Conversely, analysis of the promoter regions of the GF specific HOTAIR and HOXC13 genes exhibited high H3K4me3 and low H3K27me3 levels in GF chromatin compared to A chromatin.

Conclusions: Global transcriptome and open chromatin analyses of depot-specific preadipocytes identified their gene expression signature and differential open chromatin profile. Interestingly, A-fat-specific open chromatin regions can be observed in the proximity of GF-fat genes, but not vice versa.

Trial Registration: Clinicaltrials.gov, NCT01745471 . Registered 5 December 2012.
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http://dx.doi.org/10.1186/s13148-018-0582-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258289PMC
November 2018

Objectively measured pediatric obesity prevalence using the OneFlorida Clinical Research Consortium.

Obes Res Clin Pract 2019 Jan - Feb;13(1):12-15. Epub 2018 Nov 1.

Department of Clinical and Health Psychology, College of Public Health and Health Professions, University of Florida, Gainesville, FL, United States.

We characterized the prevalence of obesity among Florida children 2-19years old using electronic health records (EHRs). The obesity prevalence for 331,641 children was 16.9%. Obesity prevalence at 6-11years (19.5%) and 12-19years (18.9%) were approximately double the prevalence of obesity among children 2-5years (9.9%). The highest prevalence of severe obesity occurred in rural Florida (21.7%) and non-Hispanic children with multiple races had the highest obesity prevalence (21.1%) across all racial/ethnic groups. Our results highlight EHR as a low-cost alternative to estimate the prevalence of obesity and severe obesity in Florida children, both overall and within subpopulations.
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http://dx.doi.org/10.1016/j.orcp.2018.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861018PMC
April 2020

Comparative Effectiveness and Safety of Bariatric Procedures for Weight Loss: A PCORnet Cohort Study.

Ann Intern Med 2018 12 30;169(11):741-750. Epub 2018 Oct 30.

University of Pittsburgh, Pittsburgh, Pennsylvania (A.C., K.M.M.).

Background: There has been a dramatic shift in use of bariatric procedures, but little is known about their long-term comparative effectiveness.

Objective: To compare weight loss and safety among bariatric procedures.

Design: Retrospective observational cohort study, January 2005 to September 2015. (ClinicalTrials.gov: NCT02741674).

Setting: 41 health systems in the National Patient-Centered Clinical Research Network.

Participants: 65 093 patients aged 20 to 79 years with body mass index (BMI) of 35 kg/m2 or greater who had bariatric procedures.

Intervention: 32 208 Roux-en-Y gastric bypass (RYGB), 29 693 sleeve gastrectomy (SG), and 3192 adjustable gastric banding (AGB) procedures.

Measurements: Estimated percent total weight loss (TWL) at 1, 3, and 5 years; 30-day rates of major adverse events.

Results: Total numbers of eligible patients with weight measures at 1, 3, and 5 years were 44 978 (84%), 20 783 (68%), and 7159 (69%), respectively. Thirty-day rates of major adverse events were 5.0% for RYGB, 2.6% for SG, and 2.9% for AGB. One-year mean TWLs were 31.2% (95% CI, 31.1% to 31.3%) for RYGB, 25.2% (CI, 25.1% to 25.4%) for SG, and 13.7% (CI, 13.3% to 14.0%) for AGB. At 1 year, RYGB patients lost 5.9 (CI, 5.8 to 6.1) percentage points more weight than SG patients and 17.7 (CI, 17.3 to 18.1) percentage points more than AGB patients, and SG patients lost 12.0 (CI, 11.6 to 12.5) percentage points more than AGB patients. Five-year mean TWLs were 25.5% (CI, 25.1% to 25.9%) for RYGB, 18.8% (CI, 18.0% to 19.6%) for SG, and 11.7% (CI, 10.2% to 13.1%) for AGB. Patients with diabetes, those with BMI less than 50 kg/m2, those aged 65 years or older, African American patients, and Hispanic patients lost less weight than patients without those characteristics.

Limitation: Potential unobserved confounding due to nonrandomized design; electronic health record databases had missing outcome data.

Conclusion: Adults lost more weight with RYGB than with SG or AGB at 1, 3, and 5 years; however, RYGB had the highest 30-day rate of major adverse events. Small subgroup differences in weight loss outcomes were observed.

Primary Funding Source: Patient-Centered Outcomes Research Institute.
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http://dx.doi.org/10.7326/M17-2786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652193PMC
December 2018

Effect of lorcaserin on prevention and remission of type 2 diabetes in overweight and obese patients (CAMELLIA-TIMI 61): a randomised, placebo-controlled trial.

Lancet 2018 11 4;392(10161):2269-2279. Epub 2018 Oct 4.

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Background: There is a direct relationship between bodyweight and risk of diabetes. Lorcaserin, a selective serotonin 2C receptor agonist that suppresses appetite, has been shown to facilitate sustained weight loss in obese or overweight patients. We aimed to evaluate the long-term effects of lorcaserin on diabetes prevention and remission.

Methods: In this randomised, double-blind, placebo-controlled trial done in eight countries, we recruited overweight or obese patients (body-mass index ≥27 kg/m) with or at high risk for atherosclerotic vascular disease. Eligible patients were aged 40 years or older; patients at high risk for atherosclerotic vascular disease had to be aged 50 years or older with diabetes and at least one other risk factor. Patients were randomly assigned to receive either lorcaserin (10 mg twice daily) or matching placebo. Additionally, all patients had access to a standardised weight management programme based on lifestyle modification. The prespecified primary metabolic efficacy endpoint of time to incident diabetes was assessed in patients with prediabetes at baseline. The prespecified secondary outcomes for efficacy were incident diabetes in all patients without diabetes, achievement of normoglycaemia in patients with prediabetes, and change in glycated haemoglobin (HbA) in patients with diabetes. Hypoglycaemia was a prespecified safety outcome. Analysis was by intention to treat, using Cox proportional hazard models for time-to-event analyses. This trial is registered with ClinicalTrials.gov, number NCT02019264.

Findings: Between Feb 7, 2014, and Nov 20, 2015, 12 000 patients were randomly assigned to lorcaserin or placebo (6000 patients in each group) and followed up for a median of 3·3 years (IQR 3·0-3·5). At baseline, 6816 patients (56·8%) had diabetes, 3991 (33·3%) prediabetes, and 1193 (9·9%) normoglycaemia. At 1 year, patients treated with lorcaserin had a net weight loss beyond placebo of 2·6 kg (95% CI 2·3-2·9) for those with diabetes, 2·8 kg (2·5-3·2) for those with prediabetes, and 3·3 kg (2·6-4·0) for those with normoglycaemia (p<0·0001 for all analyses). Lorcaserin reduced the risk of incident diabetes by 19% in patients with prediabetes (172 [8·5%] of 2015 vs 204 [10·3%] of 1976; hazard ratio 0·81, 95% CI 0·66-0·99; p=0·038) and by 23% in patients without diabetes (174 [6·7%] of 2615 vs 215 [8·4%] of 2569; 0·77, 0·63-0·94; p=0·012). Lorcaserin resulted in a non-significant increase in the rate of achievement of normoglycaemia in patients with prediabetes (185 [9·2%] vs 151 [7·6%]; 1·20, 0·97-1·49; p=0·093). In patients with diabetes, lorcaserin resulted in a reduction of 0·33% (95% CI 0·29-0·38; p<0·0001) in HbA compared with placebo at 1 year from a mean baseline of 53 mmol/mol (7·0%). In patients with diabetes at baseline, severe hypoglycaemia with serious complications was rare, but more common with lorcaserin (12 [0·4%] vs four [0·1%] events; p=0·054).

Interpretation: Lorcaserin decreases risk for incident diabetes, induces remission of hyperglycaemia, and reduces the risk of microvascular complications in obese and overweight patients, supporting the role of lorcaserin as an adjunct to lifestyle modification for chronic management of weight and metabolic health.

Funding: Eisai.
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http://dx.doi.org/10.1016/S0140-6736(18)32328-6DOI Listing
November 2018
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