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DNA Methylation Near CPT1A and Changes in Triglyceride-rich Lipoproteins in Response to Weight-loss Diet Interventions.
Li, X, Shao, X, Xue, Q, Kou, M, Champagne, CM, Koseva, BS, Heianza, Y, Grundberg, E, Bazzano, LA, Bray, GA, et al
The Journal of clinical endocrinology and metabolism. 2023;(8):e542-e549
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Abstract
CONTEXT Carnitine palmitoyltransferase-1A, encoded by the CPT1A gene, plays a key role in the oxidation of long-chain fatty acids in the mitochondria and may be important in triglyceride metabolism. Previous work has shown that high fat intake was negatively associated with CPT1A methylation and positively associated with CPT1A expression. OBJECTIVE We aim to investigate the association of DNA methylation (DNAm) at the CPT1A gene with reductions in triglycerides and triglyceride-rich lipoproteins (TRLs) in response to weight-loss diet interventions. METHODS The current study included 538 White participants, who were randomly assigned to 1 of 4 diets varying in macronutrient components. We defined the regional DNAm at CPT1A as the average methylation level over CpGs within 500 bp of the 3 triglyceride-related DNAm sites. RESULTS Dietary fat intake significantly modified the association between baseline DNAm at CPT1A and 2-year changes in total plasma triglycerides, independent of concurrent weight loss. Among participants assigned to a low-fat diet, a higher regional DNAm level at CPT1A was associated with a greater reduction in total plasma triglycerides at 2 years (P = .01), compared with those assigned to a high-fat diet (P = .64) (P interaction = .018). Further investigation on lipids and apolipoproteins in very low-density lipoprotein (VLDL) revealed similar interaction patterns for 2-year changes in VLDL-triglycerides, VLDL-cholesterol, and VLDL-apolipoprotein B (P interaction = .009, .002, and .016, respectively), but not for VLDL-apoC-III (P interaction = .36). CONCLUSION Participants with a higher regional DNAm level at CPT1A benefit more in long-term improvement in triglycerides, particularly in the TRLs and related apolipoproteins when consuming a low-fat weight-loss diet.
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Toward Precision Weight-Loss Dietary Interventions: Findings from the POUNDS Lost Trial.
Qi, L, Heianza, Y, Li, X, Sacks, FM, Bray, GA
Nutrients. 2023;(16)
Abstract
The POUNDS Lost trial is a 2-year clinical trial testing the effects of dietary interventions on weight loss. This study included 811 adults with overweight or obesity who were randomized to one of four diets that contained either 15% or 25% protein and 20% or 40% fat in a 2 × 2 factorial design. By 2 years, participants on average lost from 2.9 to 3.6 kg in body weight in the four intervention arms, while no significant difference was observed across the intervention arms. In POUNDS Lost, we performed a series of ancillary studies to detect intrinsic factors particular to genomic, epigenomic, and metabolomic markers that may modulate changes in weight and other cardiometabolic traits in response to the weight-loss dietary interventions. Genomic variants identified from genome-wide association studies (GWASs) on obesity, type 2 diabetes, glucose and lipid metabolisms, gut microbiome, and dietary intakes have been found to interact with dietary macronutrients (fat, protein, and carbohydrates) in relation to weight loss and changes of body composition and cardiometabolic traits. In addition, we recently investigated epigenomic modifications, particularly blood DNA methylation and circulating microRNAs (miRNAs). We reported DNA methylation levels at NFATC2IP, CPT1A, TXNIP, and LINC00319 were related to weight loss or changes of glucose, lipids, and blood pressure; we also reported thrifty miRNA expression as a significant epigenomic marker related to changes in insulin sensitivity and adiposity. Our studies have also highlighted the importance of temporal changes in novel metabolomic signatures for gut microbiota, bile acids, and amino acids as predictors for achievement of successful weight loss outcomes. Moreover, our studies indicate that biochemical, behavioral, and psychosocial factors such as physical activity, sleep disturbance, and appetite may also modulate metabolic changes during dietary interventions. This review summarized our major findings in the POUNDS Lost trial, which provided preliminary evidence supporting the development of precision diet interventions for obesity management.
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Beyond BMI.
Bray, GA
Nutrients. 2023;(10)
Abstract
This review examined the origins of the concept of the BMI in the work of Quetelet in the 19th century and its subsequent adoption and use in tracking the course of the pandemic of obesity during the 20th century. In this respect, it has provided a valuable international epidemiological tool that should be retained. However, as noted in this review, the BMI is deficient in at least three ways. First, it does not measure body fat distribution, which is probably a more important guide to the risk of excess adiposity than the BMI itself. Second, it is not a very good measure of body fat, and thus its application to the diagnosis of obesity or excess adiposity in the individual patient is limited. Finally, the BMI does not provide any insights into the heterogeneity of obesity or its genetic, metabolic, physiological or psychological origins. Some of these mechanisms are traced in this review.
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Circulating thrifty microRNA is related to insulin sensitivity, adiposity, and energy metabolism in adults with overweight and obesity: the POUNDS Lost trial.
Heianza, Y, Xue, Q, Rood, J, Bray, GA, Sacks, FM, Qi, L
The American journal of clinical nutrition. 2023;(1):121-129
Abstract
BACKGROUND MicroRNA 128-1 (miR-128-1) was recently linked to the evolutionary adaptation to famine and identified as a thrifty microRNA that controls energy expenditure, contributing to obesity and impaired glucose metabolism. OBJECTIVES We investigated whether circulating miR-128-1-5p and its temporal changes in response to weight-loss diet interventions were related to regulating insulin resistance, adiposity, and energy expenditure in adults with overweight and obesity. We also examined whether habitual physical activity (PA) and different macronutrient intakes modified associations of changes in miR-128-1-5p with improved metabolic outcomes. METHODS This study included 495 adults who consumed weight-loss diets with different macronutrient intakes. Circulating levels of miR-128-1-5p were assessed at baseline and 6 mo after the interventions. Outcome measurements included changes in insulin resistance HOMA-IR, adiposity, and resting energy expenditure. RESULTS We observed significant relations between circulating miR-128-1-5p and the positive selection signals at the 2q21.3 locus assessed by the single nucleotide polymorphisms rs1446585 and rs4988235. Higher miR-128-1-5p levels were associated with greater HOMA-IR (β per 1 SD: 0.08 [SE 0.03]; P = 0.009), waist circumference (β, 1.16 [0.55]; P = 0.036), whole-body total % fat mass (β, 0.75 [0.30]; P = 0.013), and REE (β, 23 [11]; P = 0.037). In addition, higher miR-128-1-5p level was related to lower total PA index (β, -0.23 [0.07]; P = 0.001) and interacted with PA (Pinteraction < 0.05) on changes in HOMA-IR and adiposity. We found that greater increases in miR-128-1-5p levels after the interventions were associated with lesser improvements in HOMA-IR and adiposity in participants with no change/decreases in PA. Furthermore, we found that dietary fat (Pinteraction = 0.027) and protein (Pinteraction= 0.055) intakes modified relations between changes in miR-128-1-5p and REE. CONCLUSIONS Circulating thrifty miRNA was linked to regulating body fat, insulin resistance, and energy metabolism. Temporal changes in circulating miR-128-1-5p were associated with better weight-loss outcomes during the interventions; habitual PA and dietary macronutrient intake may modify such relations. This trial was registered at clinicaltrials.gov as NCT00072995.
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Sleep Disturbance and Changes in Energy Intake and Body Composition During Weight Loss in the POUNDS Lost Trial.
Li, A, Li, X, Zhou, T, Ma, H, Heianza, Y, Williamson, DA, Smith, SR, Bray, GA, Sacks, FM, Qi, L
Diabetes. 2022;(5):934-944
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To examine associations between sleep disturbance and changes in weight and body composition and the mediating role of changes of appetite and food cravings in the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) 2-year weight-loss diet intervention trial, this study included 810 overweight or obese individuals with baseline sleep disturbance assessment who were randomly assigned one of four diets varying in macronutrient composition. Changes in body weight and fat distribution were assessed by DEXA and computed tomography during the 2-year intervention. Participants were asked to provide sleep disturbance levels (no, slight, moderate, or great) at baseline and to recall their sleep disturbances since last visit at 6, 12, 18, and 24 months. Weight loss during the first 6 months was followed by 1.5 years of steady weight regain. Participants with greater sleep disturbance from baseline to 6 months showed significant losses of body weight (Ptrend <0.001) and waist circumference (Ptrend = 0.002) at 6 months, after multivariate adjustment. Compared with individuals without sleep disturbance at all from baseline to 6 months, those with slight, moderate, or great sleep disturbance showed an elevated risk of failure to lose weight (-5% or more loss) at 6 months, when the maximum weight loss was achieved, with an odds ratio of 1.24 (95% CI 0.87, 1.78), 1.27 (95% CI 0.75, 2.13), or 3.12 (95% CI 1.61, 6.03), respectively. In addition, we observed that the repeatedly measured levels of sleep disturbance over 2 years were inversely associated with the overall weight loss rate (weight changes per 6 months) (Ptrend <0.001). Further, sleep disturbances during weight loss from baseline to 6 months and weight regain from 6 months to 24 months were significantly predictive of total fat, total fat mass percent, and trunk fat percent changes during the 2 years. Our results also indicated that food cravings for carbohydrates/starches, fast food fats, and sweets; cravings, prospective consumption, hunger of appetite measurements; and dietary restraint, disinhibition, and hunger subscales measured at 6 months significantly mediated the effects of sleep disturbance on weight loss. In conclusion, our results suggested that more severe sleep disturbance during weight loss was associated with an elevated risk of failure to lose weight during the dietary intervention. Food cravings and eating behaviors may partly mediate these associations.
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Blood DNA methylation at TXNIP and glycemic changes in response to weight-loss diet interventions: the POUNDS lost trial.
Li, X, Shao, X, Bazzano, LA, Xue, Q, Koseva, BS, Grundberg, E, Shai, I, Bray, GA, Sacks, FM, Qi, L
International journal of obesity (2005). 2022;(6):1122-1127
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BACKGROUND Thioredoxin Interacting Protein (TXNIP) functions as a master regulator for glucose homeostasis. Hypomethylation at the 5'-cytosine-phosphate-guanine-3' (CpG) site cg19693031 of TXNIP has been consistently related to islet dysfunction, hyperglycemia, and type 2 diabetes. DNA methylation (DNAm) may reveal the missing mechanistic link between obesity and type 2 diabetes. We hypothesize that baseline DNAm level at TXNIP in blood may be associated with glycemic traits and their changes in response to weight-loss diet interventions. METHODS We included 639 adult participants with overweight or obesity, who participated in a 2-year randomized weight-loss diet intervention. Baseline blood DNAm levels were profiled by high-resolution methylC-capture sequencing. We defined the regional DNAm level of TXNIP as the average methylation level over CpGs within 500 bp of cg19693031. Generalized linear regression models were used for main analyses. RESULTS We found that higher regional DNAm at TXNIP was significantly correlated with lower fasting glucose, HbA1c, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) at baseline (P < 0.05 for all). Significant interactions were observed between dietary protein intake and DNAm on changes in insulin (P-interaction = 0.007) and HOMA-IR (P-interaction = 0.009) at 6 months. In participants with the highest tertile of regional DNAm at TXNIP, average protein (15%) intake was associated with a greater reduction in insulin (β: -0.14; 95% CI: -0.24, -0.03; P = 0.011) and HOMA-IR (β: -0.15; 95% CI: -0.26, -0.03; P = 0.014) than high protein (25%) intake, whereas no significant associations were found in those with the lower tertiles (P > 0.05). The interaction was attenuated to be non-significant at 2 years, presumably related to decreasing adherence to the diet intervention. CONCLUSIONS Our data indicate that higher regional DNAm level at TXNIP was significantly associated with better fasting glucose, HbA1c, and HOMA-IR; and people with higher regional DNAm levels benefited more in insulin and HOMA-IR improvement by taking the average-protein weight-loss diet.
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Genetically determined gut microbial abundance and 2-year changes in central adiposity and body composition: The POUNDS lost trial.
Li, X, Xue, Q, Ma, H, Champagne, CM, Bray, GA, Sacks, FM, Qi, L
Clinical nutrition (Edinburgh, Scotland). 2022;(12):2817-2824
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BACKGROUND AND AIM Growing evidence has linked gut microbiota with regulation of adiposity. We aimed to examine whether the genetically determined relative abundance of gut microbial taxa was associated with long-term changes in adiposity and body composition among individuals who were overweight or obese in weight-loss diet interventions. METHODS The study included 692 participants with overweight or obese from the POUNDS Lost trial. We created a genetic risk score (GRS) for the relevant abundance of gut microbial taxa using 20 single nucleotide polymorphisms identified from a recent genome-wide association study. Body composition was assessed using dual-energy X-ray absorptiometry. RESULTS Higher GRS for the relative abundance of gut microbial taxa was significantly associated with greater reductions in waist circumference, total fat mass (FM), whole-body total percentage of fat mass (FM%), and percentage of trunk fat (TF%) at 2 years (p = 0.022, 0.034, 0.023, 0.023, respectively). In addition, dietary protein significantly modified the association between GRS for gut microbial abundance and changes in total FM, FM%, and TF% (p-interactions = 0.04, 0.013, and 0.006, respectively) at 6-month, when the maximum weight loss was achieved, even though such interactions were attenuated at 2 years. In the average-protein diet group, a higher microbial abundance GRS was associated with greater reductions in total FM (p = 0.007), FM% (p = 0.002), and TF% (p < 0.001) at 6 months, while no associations were found in the high-protein diet group (p > 0.05). CONCLUSION Our results suggest that the higher genetically determined relative abundance of gut microbial taxa may be related to long-term improvement of whole-body and central fatness and body composition in response to low-calorie diet interventions.
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Changes in pedometer-measured physical activity are associated with weight loss and changes in body composition and fat distribution in response to reduced-energy diet interventions: The POUNDS Lost trial.
Xue, Q, Li, X, Ma, H, Tao, Z, Heianza, Y, Rood, JC, Bray, GA, Sacks, FM, Qi, L
Diabetes, obesity & metabolism. 2022;(6):1000-1009
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AIMS: To examine whether changes in objectively measured physical activity (PA) are associated with weight loss and changes in body composition and fat distribution in response to weight-loss diet interventions. METHODS This study included 535 participants with overweight/ obesity, who were randomly assigned to four weight-loss diets varying in macronutrients. PA was measured objectively with pedometers, and body composition and fat distribution were measured using dual-energy X-ray absorptiometry and computed tomography scans at baseline, 6 months and 24 months. RESULTS From baseline to 6 months, when the maximum weight loss was achieved, each 1000-steps/d increment in PA was associated with a greater reduction in body weight (β[SE] = -0.48[0.11]) and waist circumference (β[SE] = -0.49[0.12]). Similar inverse associations were found in changes in body composition and fat distribution (P < 0.05 and false discovery rate qvalue < 0.1 for all). The trajectory of the above adiposity measures across the 24-month intervention period differed between the patterns of PA change. Participants with the largest increase in PA maintained their weight loss from 6 months to 24 months, while those with a smaller increase in PA regained their weight. In addition, dietary fat or protein intake significantly modified the associations between changes in PA and changes in body weight and waist circumference over 24 months (P∆PA*diet < 0.05). CONCLUSIONS Changes in objectively measured PA were inversely related to changes in body weight, body composition and fat distribution in response to weight-loss diets, and such associations were more evident in people on a high-fat or average-protein diet compared with a low-fat or high-protein diet.
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Effect of 8 weeks of supervised overfeeding on eating attitudes and behaviors, eating disorder symptoms, and body image: Results from the PROOF and EAT studies.
Höchsmann, C, Fearnbach, N, Dorling, JL, Myers, CA, Zhang, D, Apolzan, JW, Stewart, TM, Bray, GA, Ravussin, E, Martin, CK
Eating behaviors. 2021;:101570
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The physiological and metabolic effects of experimental overfeeding have been extensively studied, yet only few studies have assessed overfeeding effects on eating behaviors and psychological constructs. We analyzed two 8-week overfeeding studies, the PROOF Study (N = 25; 16 males; 16 African American; 24.1 years; 25.1 kg/m2, inpatient) and the EAT Study (N = 35; 29 males; 20 White; 26.7 years; 25.5 kg/m2, free-living). In both studies, participants were overfed 40% above baseline (daily) energy requirements for eight weeks, consuming all meals under direct supervision. We assessed eating attitudes and behaviors, eating disorder symptoms, and body image via validated questionnaires and visual analog scales at baseline, week (W) 4, and W8, and at two (PROOF W16-Post, W24-Post) and three (EAT: W12-Post, W20-Post, W32-Post) follow-up visits, respectively. Hunger, desire to eat, and food cravings (carbohydrates, total cravings) decreased during overfeeding in both studies (all Cohen's d effect sizes ≥0.3, all p ≤ .048). Depressive symptoms and fear of fatness increased in both studies (all Cohen's d ≥ 0.4, p ≤ .020), though they were still within normal limits (t-scores ~43-49). Body dissatisfaction increased in both studies during overfeeding (all Cohen's d ≥ 0.4, all p ≤ .044) and remained increased during follow-up (PROOF W16-Post, Cohen's d = 0.9, p = .004; EAT: W12-Post and W20-Post, all Cohen's d ≥ 0.4, all p ≤ .037). Overfeeding was associated with some deleterious effects, though most returned to baseline during follow-up. However, increases in body dissatisfaction remained up to three months post-overfeeding, highlighting the need to address body image disturbance among people who experience weight gain, even if much of the gained weight is subsequently lost. TRIAL REGISTRATION The PROOF Study (ClinicalTrials.gov Identifier NCT00565149); the EAT Study (ClinicalTrials.gov Identifier NCT01672632).
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Genetically determined SCFA concentration modifies the association of dietary fiber intake with changes in bone mineral density during weight loss: The Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial.
Zhou, T, Sun, D, Li, X, Heianza, Y, LeBoff, MS, Bray, GA, Sacks, FM, Qi, L
The American journal of clinical nutrition. 2021;(1):42-48
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BACKGROUND SCFAs are involved in regulation of body weight and bone health. OBJECTIVES We aimed to examine whether genetic variations related to butyrate modified the relation between dietary fiber intake and changes in bone mineral density (BMD) in response to weight-loss dietary interventions. METHODS In the 2-y Preventing Overweight Using Novel Dietary Strategies trial, 424 participants with BMD measured by DXA scan were randomly assigned to 1 of 4 diets varying in macronutrient intakes. A polygenic score (PGS) was calculated based on 7 genetic variants related to the production of butyrate for 370 of the 424 participants. RESULTS SCFA PGS significantly modified the association between baseline dietary fiber intake and sex on 2-y changes in whole-body BMD (P-interaction = 0.049 and 0.008). In participants with the highest tertile of SCFA PGS, higher dietary fiber intake was related to a greater increase in BMD (β: 0.0022; 95% CI: 0.0009, 0.0035; P = 0.002), whereas no such association was found for participants in the lower tertiles. In the lowest tertiles of SCFA PGS, men showed a significant increase in whole-body BMD (β: 0.0280; 95% CI: 0.0112, 0.0447; P = 0.002) compared with women. In the highest tertile, no significant difference was found for the change in BMD between men and women. CONCLUSIONS Our data indicate that genetic variants related to butyrate modify the relations of dietary fiber intake and sex with long-term changes in BMD in response to weight-loss diet interventions.