Pennington Biomedical Research Center Research Articles

Validity of two weight prediction models for community-living patients participating in a weight loss program

Models predicting individual body weights over time clarify patient expectations in weight loss programs. The accuracy of two commonly used weight prediction models in community living people is unclear. All eligible people entering a weight management program between 1992 and 2015 were included. Patients’ diet was 1200 kcal/day for week 0 followed by 900 kcal/day for weeks 1–7 and were excluded from the analysis if they were nonadherent. We generated expected weights using the National Institutes of Health Body Weight Planner (NIH-BWP) and the Pennington Biomedical Research Center Weight Loss Predictor (PBRC-WLP). 3703 adherent people were included (mean age 46 years, 72.6% women, mean [SD] weight 262.3 pounds [54.2], mean [SD] BMI 42.4 [7.6]). Mean (SD) relative body weight differences (100*[observed−expected]/expected) for NIH-BWP and PBRC-WLP models was − 1.5% (3.8) and − 2.9% (3.2), respectively. At week 7, mean squared error with NIH-BWP (98.8, 83%CI 89.7–108.8) was significantly lower than that with PBRC-WLP (117.7, 83%CI 112.4–123.4). Notable variation in relative weight difference were seen (for NIH-BWP, 5th–95th percentile was − 6.2%, + 3.7%; Δ 9.9%). During the first 7 weeks of a weight loss program, both weight prediction models returned expected weights that were very close to observed values with the NIH-BWP being more accurate. However, notable variability between expected and observed weights in individual patients were seen. Clinicians can monitor patients in weight loss programs by comparing their progress with these data.

Editorial introductions.

Editorial introductions.

248-LB: Aging of Tanycytes Abolishes the Dynamic Regulation of Blood–Brain Barrier Permeability in the Hypothalamus

Aberrant metabolic regulation and blood-brain barrier (BBB) dysfunction are two well-known phenomena of aging. The hypothalamus is the main brain region that controls food intake and body weight. It contains a specialized BBB that allows for the free flow of blood through fenestrated capillaries in the median eminence (ME), which places a portion of neurons critical to feeding unprotected by the BBB. Aging's pernicious effect on the traditional BBB throughout the brain is well studied, however how the specialized BBB in the hypothalamus is altered with age is unknown. To study the effects of aging on hypothalamic injury and repair, we injected monosodium glutamate (MSG) into young and old mice to ablate neurons located outside the BBB. We found that in the hypothalamus of young animals, MSG led to tightening of the BBB imparted by a reduction in the number of fenestrated capillaries. In contrast, aged mice were unable to dynamically alter the BBB permeability or modulate fenestrated blood vessels in response to MSG injury. We show that hypothalamic tanycytes, radial glial-like cells lining the wall of the third ventricle, show a higher degree of physical contact with fenestrated blood vessels than with non-fenestrated blood vessels. Tanycytes in young mice following MSG exposure, modified their expression of pleiotrophin, a growth and angiogenic factor, and robustly proliferated. In comparison, tanycytes in aged mice lacked in these responses to injury, which indicate these cells undergo functional decline with aging. Moreover, aged mice following MSG lost a greater number of neurons outside the BBB and experienced severe weight loss weeks after treatment, whereas young mice showed no change in their body weight. These findings uncover that aging leads to loss of hypothalamic BBB plasticity and defective tanycytes, which increase hypothalamic vulnerability to injury and morbidity development in aged animals. Disclosure V. Pham: None. A. Xu: Advisory Panel; Pennington Biomedical Research Center, Research Support; Eli Lilly and Company. T. P. Bachor: None. Funding National Institutes on Aging (1R01AG063506-01)

1522-P: Identification of AgRP Cells in the Murine Hindbrain That Drive Feeding

The central melanocortin system is essential for the regulation of food intake and body weight in humans and rodents. Agouti-related protein (AgRP) is the sole orexigenic component of the central melanocortin system and is conserved across mammalian species. AgRP is currently known to express exclusively in the mediobasal hypothalamus, and hypothalamic AgRP-expressing neurons are essential for feeding regulation. Here we describe a previously unknown population of AgRP cells in the area postrema (AP) and the adjacent commissural nucleus of the solitary tract (cNTS) of the causal brainstem. AgRP was expressed in the embryonic AP, and hindbrain AgRP expression in adult mice was low under ad libitum fed condition but increased with food deprivation. AgRP cells in the AP and cNTS consisted of locally projecting neurons as well as tanycyte-like cells. In mice that lack hypothalamic AgRP neurons, diphtheria-toxin mediated ablation of AgRP cells led to anorexia and weight loss, whereas chemogenetic activation of AgRP neurons resulted in hyperphagia and weight gain. Moreover, focal transcranial photo-stimulation of AgRP cells in the AP and cNTS with a step-function opsin with ultra-high light sensitivity (SOUL) stimulated feeding in mice with or without hypothalamic AgRP neurons, suggesting that the hyperphagic effects of hindbrain AgRP neurons are independent of hypothalamic AgRP neurons. Collectively, our study indicates that the hindbrain has a balanced melanocortin system, complete with both orexigenic and anorexigenic components, and that AgRP neurons in the hindbrain drive feeding in adult animals. Disclosure T.P.Bachor: None. K.Attal: None. E.Vagena: None. F.Mifsud: None. V.Pham: None. M.Valdearcos-contreras: None. C.Vaisse: None. A.Xu: Advisory Panel; Pennington Biomedical Research Center, Research Support; Eli Lilly and Company. Funding National Institute of Diabetes and Digestive and Kidney Diseases (1P30DK098722-01A1, P30DK63720-06A1)

PRESIDENTIAL SYMPOSIUM: NUTRITION, METABOLISM, AND AGING

Abstract Aging is associated with increased risk for a host of non-communicable diseases and disorders including diabetes, cardiovascular disease, cancer, and neurodegeneration. Although the underlying basis for this shared risk as a function of aging is not known, numerous diseases of aging have an established metabolic component. Data from preclinical and basic research indicate that the pace of aging is malleable, and studies in short-lived species have shown the ability of genetic and nutritional interventions to not only positively impact longevity but also to prolong health into older age. This symposium, “Nutrition, Metabolism, & Aging”, features internationally renowned aging research scientists whose work focuses on how nutrition and metabolism intersect with aging biology. We will hear from John Speakman from the University of Aberdeen who will present his research on “Metabolism and Extended Longevity”; Leanne Redman from the Pennington Biomedical Research Center whose work in humans will be described in her talk on “Dietary Interventions for Healthy Aging”; Holly Brown-Borg from University of North Dakota will discuss endocrine modulation of aging in her talk “Somatotropic Signaling in Health and Longevity”; and Valter Longo from the University of Southern California who will discuss the latest findings from his research in mice and humans in his talk “Periodic Fasting in Aging and Disease". Attendees will learn about nutrition and metabolism and how these cues are interwoven to regulate aging, impact health, and enhance longevity.

Assessing the Initial Validity of the PortionSize App to Estimate Dietary Intake Among Adults: Pilot and Feasibility App Validation Study.

BackgroundAccurately assessing dietary intake can promote improved nutrition. The PortionSize app (Pennington Biomedical Research Center) was designed to quantify and provide real-time feedback on the intake of energy, food groups, saturated fat, and added sugar.ObjectiveThis study aimed to assess the preliminary feasibility and validity of estimating food intake via the PortionSize app among adults.MethodsA total of 15 adults (aged 18-65 years) were recruited and trained to quantify the food intake from a simulated meal by using PortionSize. Trained personnel prepared 15 simulated meals and covertly weighed (weigh back) the amount of food provided to participants as well as food waste. Equivalence tests (±25% bounds) were performed to compare PortionSize to the weigh back method.ResultsParticipants were aged a mean of 28 (SD 12) years, and 11 were female. The mean energy intake estimated with PortionSize was 742.9 (SD 328.2) kcal, and that estimated via weigh back was 659.3 (SD 190.7) kcal (energy intake difference: mean 83.5, SD 287.5 kcal). The methods were not equivalent in estimating energy intake (P=.18), and PortionSize overestimated energy intake by 83.5 kcal (12.7%) at the meal level. Estimates of portion sizes (gram weight; P=.01), total sugar (P=.049), fruit servings (P=.01), and dairy servings (P=.047) from PortionSize were equivalent to those estimated via weigh back. PortionSize was not equivalent to weigh back with regard to estimates for carbohydrate (P=.10), fat (P=.32), vegetable (P=.37), grain (P=.31), and protein servings (P=.87).ConclusionsDue to power limitations, the equivalence tests had large equivalence bounds. Though preliminary, the results of this small pilot study warrant the further adaptation, development, and validation of PortionSize as a means to estimate energy intake and provide users with real-time and actionable dietary feedback.

In Vivo Evaluation of the Cidec R46S Polymorphism for an Obesity QTL, tabw2a

ObjectivesA quantitative trait locus (QTL), tabw2a, was linked to obesity in TALLYHO/Jng (TH) mice, a polygenic model of obesity and type 2 diabetes. In combination with fine mapping information, we used whole genome sequencing data of TH mice to search positional candidate genes for tabw2a. From this search, the cell death-inducing DFFA-like effector c (Cidec) gene, containing a SNP identified as deleterious (likely to affect protein function) by both SIFT and PROVEAN, was raised as a potential candidate for tabw2a. CIDEC is a lipid droplet protein involved in the regulation of cellular lipid droplet size and lipid storage in adipocytes. There was one nucleotide substitution in the coding sequence of Cidec in TH mice, 136 C > A, compared to C57BL/6J (B6) reference sequence, that results in an amino acid substitution R46S (Arginine to Serine). The aim of this study was to evaluate the Cidec R46S polymorphism in vivo for the tabw2a QTL.MethodsWe generated knock-in mice where the TH allele (S46) is exchanged for the B6 allele (R46) at the Cidec gene on a B6 background. Targeting, ES clone selection, blastocyst injection, and breeding of ES cell chimeras were performed by Transgenics Core facility at Pennington Biomedical Research Center (Baton Rouge, LA). We bred the chimeras to B6 mice for 10 generation and collected heterozygous mice with germline transmission of the knock-in allele of Cidec S46. We then interbred the heterozygous mice and obtained homozygous mice for the knock-in allele of Cidec S46. Male and female Cidec R46S knock-in and B6 mice were weaned onto chow and high fat (HF) diets (D12266B, Research Diets) at 4 weeks of age and maintained on the same diets. At 20 weeks of age, body composition including fat and lean mass was measured using EchoMRI-100 whole body composition analyzer (Houston, TX).ResultsOn chow, no genotype effects were shown on adiposity between knock-in and B6 mice for both sexes. However, on HF diets, for both males and females, knock-in homozygous mice had significantly larger body fat mass than B6, although their body weights were comparable.ConclusionsWe conclude that the Cidec gene is a likely candidate for the obesity effect of tabw2a, and that Cidec S46 variant contributes to the obesity susceptibility.Funding SourcesAmerican Heart Association and National Institutes of Health.

Effects of Testosterone on Mixed-Muscle Protein Synthesis and Proteome Dynamics During Energy Deficit.

Effects of testosterone on integrated muscle protein metabolism and muscle mass during energy deficit are undetermined. The objective was to determine the effects of testosterone on mixed-muscle protein synthesis (MPS), proteome-wide fractional synthesis rates (FSR), and skeletal muscle mass during energy deficit. This was a randomized, double-blind, placebo-controlled trial. The study was conducted at Pennington Biomedical Research Center. Fifty healthy men. The study consisted of 14 days of weight maintenance, followed by a 28-day 55% energy deficit with 200 mg testosterone enanthate (TEST, n = 24) or placebo (PLA, n = 26) weekly, and up to 42 days of ad libitum recovery feeding. Mixed-MPS and proteome-wide FSR before (Pre), during (Mid), and after (Post) the energy deficit were determined using heavy water (days 1-42) and muscle biopsies. Muscle mass was determined using the D3-creatine dilution method. Mixed-MPS was lower than Pre at Mid and Post (P < 0.0005), with no difference between TEST and PLA. The proportion of individual proteins with numerically higher FSR in TEST than PLA was significant by 2-tailed binomial test at Post (52/67; P < 0.05), but not Mid (32/67; P > 0.05). Muscle mass was unchanged during energy deficit but was greater in TEST than PLA during recovery (P < 0.05). The high proportion of individual proteins with greater FSR in TEST than PLA at Post suggests exogenous testosterone exerted a delayed but broad stimulatory effect on synthesis rates across the muscle proteome during energy deficit, resulting in muscle mass accretion during subsequent recovery.

Participant Perspectives Concerning Resuming Clinical Research in the Era of COVID-19.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic caused a shutdown of clinical research but offered a unique opportunity to understand attitudes and motivations around contributing to clinical research and resuming in-person visits during a pandemic.MethodsWe conducted an anonymous survey study at Pennington Biomedical Research Center (PBRC) in participants returning for in-person visits from May 26, 2020 to August 11, 2020 and in people who previously expressed interest in research via an online Research Electronic Data Capture (REDCap) survey from August 6, 2020 to September 11, 2020. The survey gathered demographic information and presented statements that required answers on a scale of 1 (absolutely disagree) to 10 (absolutely agree). Two hundred fifty-one people completed paper surveys in-person while 1,537 people completed the survey online.ResultsOnline participants were more likely to be female (75.2% vs. 56.8%), more likely to have had COVID-19 symptoms (19.6% vs. 5.2%), and more likely to know someone with COVID-19 (72.7% vs. 49.4%). More people who came in-person thought they were low risk for severe COVID-19 compared to those who filled out the survey online (52.2% vs. 38.4%, P = 0.0002). More people who completed the survey online preferred to do as many study visits over the phone or internet as possible (37.8% vs. 22.7%, P < 0.0001). More people who came in-person agreed that clinical research is even more important than before COVID-19 (54.2% vs. 44.3%, P = 0.0035).ConclusionsThe majority of people felt that clinical research is important because of the health benefits received and because it may help others. These data may provide important considerations in the planning of future studies in the era of COVID-19.

Impact of COVID-19 Stay-at-Home Orders on Health Behaviors and Anxiety in Black and White Americans.

BackgroundIn the United States (US), the incidence and severity of COVID-19 infections, hospitalizations, and deaths are higher in Black compared to White residents. Systemic inequities and differences in health behaviors may contribute to disparities in COVID-19 health outcomes. The aim of this study was to examine the impact of COVID-19 stay-at-home orders on changes in health behaviors and anxiety in Black and White adults residing in the US.MethodsBeginning April 2020, the Pennington Biomedical Research Center COVID-19 Health Behaviors Study collected information on changes to employment, income, diet, physical activity, anxiety, and sleep patterns through a global online survey.ResultsOf 4542 survey respondents in the US, 7% identified as Black and 93% as White. Prior to the COVID-19 stay-at-home orders, a greater proportion of Blacks compared to Whites reported earning < US$50,000 per year (p < 0.0001). A greater proportion of Blacks reported being laid off, working fewer hours, and working from home following COVID-19 stay-at-home orders (p < 0.0001 for all). In the overall sample, eating behaviors improved, physical activity decreased, sleep time prolonged, and anxiety heightened following COVID-19 stay-at-home orders (p < 0.01 for all), which were universal between Black and White respondents (p ≥ 0.315 for all).ConclusionsThis study highlights the disproportionate changes to employment and income in Blacks, with no differential impact on health behaviors and anxiety compared to Whites due to COVID-19 stay-at-home orders. As the COVID-19 pandemic continues, disproportionate changes to employment and income status may widen among Blacks and Whites, which may influence health behaviors and anxiety.

DNAJB3 Deficiency Exacerbates Diet-Induced Obesity and Insulin Resistance

ObjectivesThe prevalence of obesity and Type 2 Diabetes (T2D) continues to rise worldwide, leading to many other chronic diseases and imposing a large economic burden. DNAJ, also known as HSP40 (Heat Shock Protein-40), subfamily B, member 3 (DNAJB3), is a chaperone protein that can be induced under various stressors. Recent reports implicated DNAJB3 in protection against obesity and T2D. Specifically, DNAJB3 was downregulated in some patients with obesity and T2D; however, precise underlying mechanisms remained unclear. We hypothesized that lack of DNAJB3 will increase body weight and body fat, inflammation, glucose intolerance and insulin resistance in diet-induced obese mice, compared to B6 wild type (WT) littermates fed the same diets. MethodsThree DNAJB3 knockout (KO) mutant lines were generated at the Pennington Biomedical Research Center (KO 30, 44 and 47). Male and female KO and wild type (WT) littermates were fed a high fat diet (45% kcal fat) for 12 weeks. Body weight and composition were measured weekly, and a glucose tolerance test (GTT) was conducted. Following euthanasia, blood, adipose and muscle tissues were harvested and used for serum analyses and tissue gene/protein expression, respectively. ResultsCompared to WT, only DNAJB3 KO male and female mice of line 47 demonstrated significantly higher body weight and fat mass (P < 0.05). Similarly, line 47 also showed a lower rate of glucose clearance as measured by GTT. Consistent with increased body weight and fat mass, male mice in line 47 also exhibited significantly higher mRNA levels of inflammatory markers including TNFα and IL-1β, in gonadal fat, compared to WT and lines 30 and 44. Moreover, similar trends towards increased TNF-α and MCP-1 expression was observed in muscle tissues of KO males of line 47, when compared to WT (P < 0.47), and line 30 (P < 0.15) respectively. ConclusionsAbsence of DNAJB3, increases adiposity, glucose intolerance and inflammation in diet-induced obese mice in both males and females. these findings suggest that DNAJB3 plays an important role in metabolic functions and glucose homeostasis, which warrants further research as a potential therapeutic target for obesity and T2D. Funding SourcesFunded by Qatar National Research Funds, Hamad Bin Khalifa University & Qatar Biomedical Research Institute, Qatar.

Calorie Restriction Improves Lipid-Related Emerging Cardiometabolic Risk Factors in Healthy Non-Obese Adults: Distinct Influences of BMI and Sex From CALERIE™ - A Multicentre, Phase 2, Randomised Controlled Trial

Background: For many cardiovascular risk factors there is no lower limit to which further reduction will result in decreased disease risk; this includes values extending ranges of normal healthy adults. This seems to be true for new emerging metabolic risk factors identified by innovative technological advances. Further, there seems to be ever evolving evidence of differential responses to lifestyle interventions by sex and body compositions in the normal range. In this secondary analysis, we had the opportunity to test these principles for newly identified molecular biomarkers of cardiometabolic risk in a young, normal weight healthy population undergoing calorie restriction for two years. Methods: The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) was a 24-month, randomized controlled trial in healthy, non-obese adults to evaluate the potential for calorie restriction (CR) to promote anti-aging adaptations, including those associated with disease risk. 218 participants (age 37.9±7.19 years and BMI 25.1±1.73 kg/m2, mean±SD) were randomized 2:1 to 24 months of CR (prescribed as 25% reduction from baseline calorie intake) versus ad libitum (AL). Fasting plasma from baseline, 12, and 24 months was used for assessments of lipoproteins, metabolites, and inflammatory markers using nuclear magnetic resonance spectroscopy.­­­­­­­­­ Results: Averaging 11.9% CR, the CR group had reductions at 12 and 24 months in the cardiovascular disease risk markers, apolipoprotein B and GlycA, and risks for insulin resistance and type 2 diabetes—Lipoprotein Insulin Resistance Index and Diabetes Risk Index (all PCRvsAL ≤0.0009). Insulin resistance and diabetes risk improvements resulted from CR-induced alterations in lipoproteins, specifically reductions in triglyceride-rich lipoprotein particles and LDL particles, a shift to larger HDL particles (more effective cholesterol transporters), and reductions in branched chain amino acids (BCAAs) (all PCRvsAL ≤0.004). These CR responses were more pronounced in overweight than normal weight participants and greater in men than women. Conclusions: In normal to slightly overweight adults without overt risk factors or disease, 12 months of ~12% CR improved risks of atherosclerotic cardiovascular disease, insulin resistance and type 2 diabetes. These CR-mediated benefits accrued via reduced inflammation and branched chain amino acids, and a shift from atherogenic to cholesterol transporting lipoproteins. Additionally, CR benefits were influenced by sex and BMI, factors meriting close attention in future investigations of lifestyle-mediated improvements in disease risk factors. Clinical Trial Registration Details: NCT00427193. Funding Information: CALERIETM was conducted as a National Institutes of Health (NIH) U-grant (U01 AG022132, U01 AG020478, U01 AG020487 U01 AG020480 ). As defined by this mechanism, the study design and conduct was a collaborative effort between internal NIH and external study investigators. Additional project funding was provided by NIH R01 AG054840 (MO, VBK); R33 AG070455 (KMH, DCP, MB, SBR, CKM, LMR, SKD, CFP, CJR, WEK); P30 DK072476 (CKM, LMR); and U54 GM104940 (CKM, LMR) and without any additional scientific contribution or other role in this report. Declaration of Interests: MAC, IS, and JDO are employees of Labcorp. All other authors have no conflicts interests. Ethics Approval Statement: The study protocol (NCT00427193) was approved by the institutional review boards at all participating clinical centers (Washington University School of Medicine, St Louis, MO; Pennington Biomedical Research Center, Baton Rouge, LA; Tufts University, Boston, MA), and the coordinating center (Duke University, Durham, NC). All study participants provided written informed consent and study oversight was provided by a Data and Safety Monitoring Board.

Muscle Echogenicity and Changes Related to Age and Body Mass Index.

Muscle fibers are lost and replaced by fat- and fibrous-tissue infiltration during aging. This process decreases muscle quality and influences tissue appearance on ultrasound images over time. Increased muscle "echogenicity" represents changes caused by fat- and fibrous-tissue infiltration and can be quantified with recently developed software. To investigate skeletal muscle quality through echogenicity, estimates according to participant's body mass index (BMI) and age were taken. This was a cross-sectional study performed at the Pennington Biomedical Research Center, Baton Rouge, Louisiana with 117 participants (57 men and 60 women), with mean age (±SD) 38.9 ± 17.0 years and BMI 28.6 ± 6.2 kg/m². All participants were examined by ultrasound (LOGIQ GE Healthcare), using a 5.0-MHz linear transducer. Participants had muscle thickness measured by ultrasound at 4 anatomic locations (biceps and triceps brachial, femoral quadriceps, and calf triceps). Echogenicity was analyzed with specific software (Pixel Health) that evaluated the image in gray scale. According to BMI, 41% of participants were obese. There was a positive correlation between age and thigh-muscle echogenicity (rp = 0.534, P < .0001) and a negative correlation between thigh-muscle echogenicity and thickness (rp = -0.395, P <.0001). There was high muscle echogenicity in participants with overweight and obesity aged 50 years or older (P < .05). Older age and higher BMI were associated with stronger echogenicity signals and smaller muscle thickness. People with overweight, obesity, and/or older than 50 years old have reduced muscle quality with smaller muscle thickness, as observed with ultrasound.

Adipose depot-specific effects of 16weeks of pioglitazone on in vivo adipogenesis in women with obesity: a randomised controlled trial.

In vitro and rodent studies suggest that pioglitazone, a thiazolidinedione, can promote adipogenesis in adipose tissue (AT); however, there is a lack of in vivo studies in humans to support these findings. The objectives of this randomised, placebo-controlled, parallel-arm trial were to test if pioglitazone stimulates in vivo adipogenesis in the subcutaneous adipose tissue depots and if these measures were related to metabolic health outcomes in women with obesity. Forty-one healthy women with obesity (20 black; 21 white; 29 ± 6years; BMI 32.0 ± 1.7kg/m2; 44.0 ± 3.6% body fat) were randomised to consume 30mg/day of pioglitazone (n = 21) or placebo (n = 20) for 16weeks. SAS v9.4 was used to generate the block randomisation code sequence (stored in password-protected files) with a 1:1 allocation ratio. The participants and study staff involved in assessing and analysing data outcomes were blinded to the group assignments. The trial was conducted at Pennington Biomedical Research Center and ended in 2016. At baseline and post-intervention, subcutaneous abdominal (scABD) and femoral (scFEM) AT biopsies were collected, and in vivo cellular kinetics (primary endpoint of the trial) were assessed by an 8week labelling protocol of deuterium (2H) into the DNA of adipose cells. Body composition was measured by dual-energy x-ray absorptiometry (DXA), scABD and visceral AT (VAT) by MRI, ectopic fat by 1H-MRS, and insulin sensitivity by an OGTT. After the 16week intervention, there was a significant decrease in visceral fat (VAT:total abdominal AT [as a %]; p = 0.002) and an increase in the Matsuda index (i.e. improved insulin sensitivity; p = 0.04) in the pioglitazone group relative to the placebo group. A significant increase in the formation of new adipocytes was observed in the scFEM (Δ = 3.3 ± 1.6%; p = 0.04) but not the scABD depot (Δ = 2.0 ± 2.1%; p = 0.32) in the pioglitazone group relative to the placebo group. No serious adverse events were reported. Pioglitazone may elicit distinct differences in in vivo adipogenesis in subcutaneous adipose depots in women with obesity, with increased rates in the protective scFEM. Trial registration ClinicalTrials.gov NCT01748994 Funding This study was funded by R01DK090607, P30DK072476, and R03DK112006 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health. The Robert C. and Veronica Atkins Foundation. Graphical abstract.

Effect of conjugated estrogens and bazedoxifene on glucose, energy and lipid metabolism in obese postmenopausal women.

Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. Randomized, double-blind, crossover pilot trial with washout was conducted at Pennington Biomedical Research Center. Eight postmenopausal women (age 50-60 years, BMI 30-40 kg/m2) were randomized to 8 weeks CE/BZA or placebo. Primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp). Secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); serum inflammatory markers; and serum metabolome (LC/MS). CE/BZA treatment produced no detectable effect on insulin sensitivity, body composition, ectopic fat, fat cell size, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: P = 0.06; high-dose clamp: P = 0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein (HDL)-cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs) and decreased long-chain acylcarnitines, possibly reflecting increased hepatic de novo FA synthesis and esterification into TAGs for export into very low-density lipoproteins, as well as decreased FA oxidation, respectively (P < 0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in serum lipoproteins (P < 0.05). A short treatment of obese postmenopausal women with CE/BZA does not alter insulin action or ectopic fat but increases serum markers of hepatic de novo lipogenesis and TAG production.

687-P: Support Vector Regression Model Predicts Glucose Changes during Exercise in Type 1 Diabetes

People with type 1 diabetes (T1D) have difficulty controlling glucose during exercise. Different types, intensities, and durations of exercise impact glucose differently. There is currently no algorithm that can accurately predict glucose changes during aerobic, resistance, interval, and free-living exercise. A support vector regression (SVR) model was designed to predict the maximum change in glucose during exercise. The model was trained and validated on 30-minute exercise sessions collected twice weekly over 4 weeks from 33 people with T1D (age 33±13 years, BMI 26.3±2.9 kg/m2, 18±12 years since diagnosis). Participants completed study assigned aerobic (n = 40), resistance (n= 33), or interval (n=20) exercise sessions in addition to their typical exercise regimen (n = 254). Participants wore a Dexcom (G5 or G6) or Medtronic CGM and used their own insulin pen (n = 10) or pump to administer insulin. The exercise information and food consumed was reported using a custom app. Heart rate, accelerometry, and sleep metrics were acquired using a Garmin vivosmart watch. Training was done on 90% of the observations while 10% of data were used for testing using 10-fold cross validation. The mean absolute error (MAE) of the model-predicted change in glucose during exercise was 23.59 mg/dL. The SVR algorithm may be useful within a decision support tool to help people with T1D better manage their glucose levels during exercise. Disclosure G. Young: None. Z. Li: None. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. R.L. Gal: None. R. Beck: None. J.R. Castle: Advisory Panel; Self; Novo Nordisk Inc. Consultant; Self; ADOCIA, Dexcom, Inc., Zealand Pharma A/S. Other Relationship; Self; Pacific Diabetes Technologies, Roche Diabetes Care. M.A. Clements: Consultant; Self; Glooko, Inc. Other Relationship; Self; Glooko, Inc. E. Dassau: Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc., DreaMed Diabetes, Tandem Diabetes Care, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; Roche Diabetes Care. Other Relationship; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care. F.J. Doyle: Research Support; Self; DreaMed Diabetes, Tandem Diabetes Care, Xeris Pharmaceuticals, Inc. Stock/Shareholder; Self; Mode AGC. Other Relationship; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care. M.B. Gillingham: None. C.K. Martin: Advisory Panel; Self; EHE Health, NaturallySlim. Consultant; Self; Florida Hospital, Gila Therapeutics, OpenFit, Zafgen, Inc. Research Support; Self; Egg Board, Helmsley Trust, IDEA Public Schools, National Institutes of Health, NIHR, Patient-Centered Outcomes Research Institute, USDA, Weight Watchers International, Inc. Other Relationship; Self; Academy of Nutrition and Dietetics, Louisiana State Univ./Pennington Biomedical Research Center. M.R. Rickels: Consultant; Self; Semma Therapeutics, Inc. Research Support; Self; Xeris Pharmaceuticals, Inc. S.R. Patton: None. M. Riddell: Advisory Panel; Self; Zucara Therapeutics Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation. Speaker’s Bureau; Self; Medtronic, Novo Nordisk A/S. P.G. Jacobs: Consultant; Self; SFC Fluidics. Research Support; Self; Dexcom, Inc. Stock/Shareholder; Self; Pacific Diabetes Technologies. Other Relationship; Self; AgaMatrix. Funding Exercise in Diabetes Initiative (T1-DEXI Main Study)

694-P: Effect of Exercise on Sleep and Nocturnal Glucose in Type 1 Diabetes (T1D)

Exercise increases nocturnal hypoglycemia risk which may impact sleep in T1D. Adults with T1D (n=25; 19 CSII; age 33±14yrs; HbA1c 7.6±1.3%; T1D duration 15yrs [IQR: 10, 22]) were divided into 3 exercise groups: aerobic, interval, or resistance, performed twice/week using instructional videos for 4 weeks. Participants used CGM, and wore an activity/sleep monitor (Garmin Vivosmart 3). Sleep duration was lower on nights following interval exercise compared to nights following sedentary days (p=0.04, Figure 1a). Participants experienced hypoglycemia earlier in the night following interval or aerobic exercise, compared to sedentary or resistance exercise (Figure 1b). Exercise types differentially impact sleep loss and nocturnal hypoglycemia. Disclosure P.G. Jacobs: Consultant; Self; SFC Fluidics. Research Support; Self; Dexcom, Inc. Stock/Shareholder; Self; Pacific Diabetes Technologies. Other Relationship; Self; AgaMatrix. Z. Li: None. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. R.L. Gal: None. R. Beck: None. J.R. Castle: Advisory Panel; Self; Novo Nordisk Inc. Consultant; Self; ADOCIA, Dexcom, Inc., Zealand Pharma A/S. Other Relationship; Self; Pacific Diabetes Technologies, Roche Diabetes Care. M.A. Clements: Consultant; Self; Glooko, Inc. Other Relationship; Self; Glooko, Inc. E. Dassau: Consultant; Self; Eli Lilly and Company. Research Support; Self; Dexcom, Inc., DreaMed Diabetes, Tandem Diabetes Care, Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; Roche Diabetes Care. Other Relationship; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care. F.J. Doyle: Research Support; Self; DreaMed Diabetes, Tandem Diabetes Care, Xeris Pharmaceuticals, Inc. Stock/Shareholder; Self; Mode AGC. Other Relationship; Self; Dexcom, Inc., Insulet Corporation, Roche Diabetes Care. M.B. Gillingham: None. C.K. Martin: Advisory Panel; Self; EHE Health, NaturallySlim. Consultant; Self; Florida Hospital, Gila Therapeutics, OpenFit, Zafgen, Inc. Research Support; Self; Egg Board, Helmsley Trust, IDEA Public Schools, National Institutes of Health, NIHR, Patient-Centered Outcomes Research Institute, USDA, Weight Watchers International, Inc. Other Relationship; Self; Academy of Nutrition and Dietetics, Louisiana State Univ./Pennington Biomedical Research Center. M.R. Rickels: Consultant; Self; Semma Therapeutics, Inc. Research Support; Self; Xeris Pharmaceuticals, Inc. S.R. Patton: None. M. Riddell: Advisory Panel; Self; Zucara Therapeutics Inc. Consultant; Self; Lilly Diabetes. Research Support; Self; Dexcom, Inc., Insulet Corporation. Speaker’s Bureau; Self; Medtronic, Novo Nordisk A/S. Funding The Leona M. and Harry B. Helmsley Charitable Trust (T1-DEXI Main Study)

Growth Differentiation Factor 15 Is Linked to Reduced Preference for Fatty Foods in Adults with Overweight or Obesity

Abstract Objectives Growth differentiation factor 15 (GDF15) reduces food intake, dietary fat preference, and body weight in pre-clinical studies. Through recent human and in vitro studies, we have identified a role for GDF15 in the energy expenditure (exercise) side of the energy balance equation. Collectively, GDF15 has emerged as a novel candidate for the treatment of human obesity. However, whether GDF15 regulates food intake or food preference in humans remains to be elucidated. Herein, we hypothesized that fasting and exercise-induced GDF15 plasma concentrations would be related to habitual food intake and preference in adults with overweight/obesity. Methods Samples previously collected from eleven adults (age: 54 ± 3, BMI: 32.4 ± 1.6, kg/m2, six women, five men) were subjected to secondary analysis. Fasting plasma GDF15 was quantified by ELISA, while habitual diet was measured from 3-day dietary records. Dietary data was analyzed by the Dietary Analysis Core at Pennington Biomedical Research Center using FNDDS (USDA 2015–2016). A sub-cohort (n = 9) further completed a 7-day aerobic exercise training for 60 min/day at ∼85% HRmax, GDF15 assessment was repeated post-training. Results At baseline, GDF15 showed trends in reduced total energy intake (kcals, R = −0.40, P = 0.22), and was inversely associated with fatty foods (oils, g/day) (R = −0.62, P &amp;lt; 0.05), consistent with animal models. Exercise increased GDF15 in six adults (responders), but decreased in three adults (non-responders). Responders habitually consumed 52% less total fat (g/1000kcals, P = 0.01) and 59% less oils (g/1000kcals, P = 0.01) compared to non-responders. In agreement, exercise-induced changes in GDF15 negatively associated with baseline fat (kcal/g, R = −0.68, P &amp;lt; 0.05) and cheese (serving/kcal, R = −0.67, P &amp;lt; 0.05) intake. Conclusions This study provides preliminary evidence that GDF15 is linked to reduced fatty food preference in adults with overweight or obesity, suggesting a promising anti-obesity effect of GDF15 in humans. Larger human trials with repeated measurements are warranted to further elucidate the response. Funding Sources The study was supported by the National Institute of Health: UL1RR024989, U54GM104940, DK108089 (JPK) and T32AT004094 (JTM – trainee).

Resistant Starch Has No Effect on Appetite and Food Intake in Individuals with Prediabetes

BackgroundType 2 resistant starch (RS2) has been shown to improve metabolic health outcomes and may increase satiety and suppress appetite and food intake in humans. ObjectiveThis study assessed whether 12 weeks of daily RS2 supplementation could influence appetite perception, food intake, and appetite-related gut hormones in adults with prediabetes, relative to the control (CTL) group. DesignThe study was a randomized controlled trial and analysis of secondary study end points. Participants/settingSixty-eight adults (body mass index ≥27) aged 35 to 75 years with prediabetes were enrolled in the study at Pennington Biomedical Research Center (2012 to 2016). Fifty-nine subjects were included in the analysis. InterventionParticipants were randomized to consume 45 g/day of high-amylose maize (RS2) or an isocaloric amount of the rapidly digestible starch amylopectin (CTL) for 12 weeks. Main outcome measuresSubjective appetite measures were assessed via visual analogue scale and the Eating Inventory; appetite-related gut hormones (glucagon-like peptide 1, peptide YY, and ghrelin) were measured during a standard mixed-meal test; and energy and macronutrient intake were assessed by a laboratory food intake (buffet) test, the Remote Food Photography Method, and SmartIntake app. Statistical analyses performedData were analyzed using linear mixed models, adjusting for treatment group and time as fixed effects, with a significance level of α=.05. ResultsRS2 had no effect on subjective measures of appetite, as assessed by visual analogue scale (P>0.05) and the Eating Inventory (P≥0.24), relative to the CTL group. There were no effects of RS2 supplementation on appetite-related gut hormones, including glucagon-like peptide 1 (P=0.61), peptide YY (P=0.34), and both total (P=0.26) and active (P=0.47) ghrelin compared with the CTL. RS2 had no effect on total energy (P=0.30), carbohydrate (P=0.11), protein (P=0.64), or fat (P=0.37) consumption in response to a buffet meal test, relative to the CTL. In addition, total energy (P=0.40), carbohydrate (P=0.15), protein (P=0.46), and fat (P=0.53) intake, as quantified by the Remote Food Photography Method, were also unaffected by RS2, relative to the CTL. ConclusionsRS2 supplementation did not increase satiety or reduce appetite and food intake in adults with prediabetes.

Testosterone Administration During Energy Deficit Suppresses Hepcidin and Increases Iron Availability for Erythropoiesis

Severe energy deprivation markedly inhibits erythropoiesis by restricting iron availability for hemoglobin synthesis. The objective of this study was to determine whether testosterone supplementation during energy deficit increased indicators of iron turnover and attenuated the decline in erythropoiesis compared to placebo. This was a 3-phase, randomized, double-blind, placebo-controlled trial. The study was conducted at the Pennington Biomedical Research Center. Fifty healthy young males. Phase 1 was a 14-day free-living eucaloric controlled-feeding phase; phase 2 was a 28-day inpatient phase where participants were randomized to 200 mg testosterone enanthate/week or an isovolumetric placebo/week during an energy deficit of 55% of total daily energy expenditure; phase 3 was a 14-day free-living, ad libitum recovery period. Indices of erythropoiesis, iron status, and hepcidin and erythroferrone were determined. Hepcidin declined by 41%, indicators of iron turnover increased, and functional iron stores were reduced with testosterone administration during energy deficit compared to placebo. Testosterone administration during energy deficit increased circulating concentrations of erythropoietin and maintained erythropoiesis, as indicated by an attenuation in the decline in hemoglobin and hematocrit with placebo. Erythroferrone did not differ between groups, suggesting that the reduction in hepcidin with testosterone occurs through an erythroferrone-independent mechanism. These findings indicate that testosterone suppresses hepcidin, through either direct or indirect mechanisms, to increase iron turnover and maintain erythropoiesis during severe energy deficit. This trial was registered at www.clinicaltrials.gov as #NCT02734238.