Author + information
- Received December 16, 2009
- Revision received February 22, 2010
- Accepted March 9, 2010
- Published online August 17, 2010.
- Abel Romero-Corral, MD, MS⁎,
- Fatima H. Sert-Kuniyoshi, PhD⁎,
- Justo Sierra-Johnson, MD, PhD‡,
- Marek Orban, MD⁎,
- Apoor Gami, MD⁎,
- Diane Davison, RN⁎,
- Prachi Singh, PhD⁎,
- Snigdha Pusalavidyasagar, MD⁎,
- Christine Huyber⁎,
- Susanne Votruba, PhD†,
- Francisco Lopez-Jimenez, MD, MSc⁎,
- Michael D. Jensen, MD† and
- Virend K. Somers, MD, PhD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Virend K. Somers, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905
Objectives The aim of this study was to determine the impact of fat gain and its distribution on endothelial function in lean healthy humans.
Background Endothelial dysfunction has been identified as an independent predictor of cardiovascular events. Whether fat gain impairs endothelial function is unknown.
Methods A randomized controlled study was conducted to assess the effects of fat gain on endothelial function. Forty-three normal-weight healthy volunteers were recruited (mean age 29 years; 18 women). Subjects were assigned to gain weight (approximately 4 kg) (n = 35) or to maintain weight (n = 8). Endothelial function (brachial artery flow-mediated dilation [FMD]) was measured at baseline, after fat gain (8 weeks), and after weight loss (16 weeks) for fat gainers and at baseline and follow-up (8 weeks) for weight maintainers. Body composition was measured by dual-energy X-ray absorptiometry and abdominal computed tomographic scans.
Results After an average weight gain of 4.1 kg, fat gainers significantly increased their total, visceral, and subcutaneous fat. Blood pressure and overnight polysomnography did not change after fat gain or loss. FMD remained unchanged in weight maintainers. FMD decreased in fat gainers (9.1 ± 3% vs. 7.8 ± 3.2%, p = 0.003) but recovered to baseline when subjects shed the gained weight. There was a significant correlation between the decrease in FMD and the increase in visceral fat gain (rho = −0.42, p = 0.004), but not with subcutaneous fat gain (rho = −0.22, p = 0.15).
Conclusions In normal-weight healthy young subjects, modest fat gain results in impaired endothelial function, even in the absence of changes in blood pressure. Endothelial function recovers after weight loss. Increased visceral rather than subcutaneous fat predicts endothelial dysfunction. (Fat Gain and Cardiovascular Disease Mechanisms; NCT00589498)
Endothelial dysfunction is considered a systemic process and an early event in the atherosclerotic process (1). Brachial artery flow-mediated dilation (FMD) reflects coronary endothelial function (2,3) and has been associated with a higher prevalence of coronary artery disease (1) and is an independent predictor of cardiovascular events in patients with and without established atherosclerosis (4,5).
Increased body fat has been linked to a higher risk for cardiovascular disease. Previous studies assessing obesity and endothelial dysfunction have been cross-sectional in nature, and thus no causal interaction can be defined (6,7). Although visceral obesity is predictive of increased cardiovascular risk, there are no data on the interactions between visceral obesity and endothelial function. We tested the hypothesis that endothelial function is impaired after weight gain and recovers after reversal of weight gain. We also tested the hypothesis that impaired endothelial function is linked to visceral or subcutaneous fat accumulation.
We recruited 43 healthy volunteers with baseline body mass indexes (BMIs) of 18.5 to 24.9 kg/m2. Subjects were excluded if they were smokers, were pregnant, were taking any medication, or had any acute or chronic illness. This study was approved by the Mayo Clinic institutional review board, and all subjects provided written informed consent.
Fat gainer and weight maintainer protocols
After a weight maintenance period of 3 days, subjects were randomly assigned to be in the fat gainer or weight maintainer group, with a 20% chance of being a weight maintainer. For the fat gainer group, for the first 8 weeks, each subject received 1,000 kcal/day (40% carbohydrate, 40% fat, and 20% protein) in addition to weight maintenance requirements. The goal was to gain 3 to 4 kg of total body fat (a 5% increase in weight). After the fat gain, subjects underwent a diet program to return to their basal weights. Dietary counseling was available to all participants, and their weights were monitored by a dietitian throughout the study. Exercise treadmill testing was conducted to assess changes in levels of physical fitness during the study.
We measured height by wall stadiometer, weight by electronic scale, and waist and hip circumferences by nonelastic tape. The volunteers underwent computed tomographic measures of visceral fat area (single-slice computed tomography at the L2 to L3 interspace) and dual-energy X-ray absorptiometry (Lunar Radiation, Madison, Wisconsin) at baseline and after 8 weeks for both groups and after weight loss (16 weeks) for fat gainers. For logistic reasons, computed tomographic and dual-energy X-ray absorptiometry measures were obtained in all 35 subjects before and after weight gain and in 16 subjects after weight loss.
All subjects were asked to abstain from alcohol and caffeine for 24 h before the study. Subjects underwent complete overnight polysomnography to exclude the development of sleep apnea using the apnea-hypopnea index (events/h) (8) with weight gain. FMD was measured in the morning with the subjects fasting, with high-resolution ultrasound following a standard protocol as previously described (9).
Blood samples were obtained at the 3 time points. Leptin was measured using a radioimmunoassay kit (Linco Research, Inc., St. Louis, Missouri), insulin was measured using a 2-site immunoenzymatic assay (Beckman Instruments, Inc., Chaska, Minnesota), adiponectin was measured using an enzyme-linked immunosorbent assay kit (Mediagnost GmbH, Reutlingen, Germany), glucose was measured using hexokinase reagent using a Hitachi 912 chemistry analyzer (Boehringer Mannheim, Indianapolis, Indiana), and lipid profile (cholesterol, triglycerides, and high-density lipoprotein) was measured using the standard turbidometry method on a Hitachi 912 chemistry analyzer (Roche Diagnostics GmbH, Mannheim, Germany). High-sensitivity C-reactive protein (CRP) was measured on a Hitachi 912 chemistry analyzer using a polystyrene particle-enhanced immunoturbidometric assay (DiaSorin, Saluggia, Italy).
Data are summarized as mean ± SD for quantitative variables and as numbers and percents for categorical variables. The changes between baseline and after 8 weeks were compared using paired t test analyses. An additional analysis was performed for fat gainers after weight loss. We used an unpaired t test to compare fat gainers and weight maintainers at baseline and at 8 weeks (a nonparametric test showed similar results). Because of the nonlinearity of the data, we used Spearman's correlation coefficients between the changes in FMD with total, visceral, and subcutaneous fat gain, and changes in cardiometabolic biomarkers.
Finally, we divided into tertiles the amount of visceral and subcutaneous fat gained to assess the relationship between magnitude of fat gain and changes in FMD among fat gainers. Data were analyzed using JMP (SAS Institute Inc., Cary, North Carolina). Two-tailed p values <0.05 were considered significant. Bonferroni's correction was used to adjust for multiple comparisons, and a 2-tailed p < 0.016 was considered significant.
We recruited 43 lean healthy volunteers, 35 fat gainers and 8 weight maintainers. The mean age was 29 ± 6 years, and 18 (42%) were women. Fat gainers were slightly older than weight maintainers (age 26 ± 3 years vs. 29 ± 7 years, p = 0.05), but there were no other significant differences between the 2 groups (Table 1).
There were no differences in any variable measured between baseline and 8 weeks after the weight maintenance period (Table 1).
After an average weight gain of 4.1 ± 0.20 kg, of which >80% was fat, total body, visceral, and subcutaneous fat area and total body fat percent increased significantly (all p values <0.0001). After an average of 3.6 kg weight loss at recovery, anthropometric and body composition measures recovered to baseline values (all p values >0.05). Neither weight gain nor weight loss resulted in significant changes in resting blood pressure or heart rate (Table 1).
In the fat gainers, FMD diminished significantly (9.1 ± 3.0 vs. 7.6 ± 3.2, p = 0.003) and recovered to baseline (9.0 ± 3.8) after losing the gained weight (Fig. 1). In the weight maintainers, FMD remained unchanged during the study (p = 0.45) (Table 1).
Changes in endothelial function as measured by percent change in FMD after weight gain were not significantly correlated with changes in cardiometabolic biomarkers (Table 2).
We found a significant and negative correlation between percent changes in FMD and total fat gain (rho = −0.45, p = 0.002) in the abdominal area. After analyzing visceral and subcutaneous fat separately, visceral (rho = −0.42, p = 0.004) but not subcutaneous (rho = −0.22, p = 0.15) fat gain was significantly related to reduction of FMD. Furthermore, the magnitude of impairment in FMD was significantly higher in subjects who had greater increases in visceral fat (Fig. 2). Total body fat, BMI, waist circumference, and waist-to-hip ratio increments were not related to changes in FMD.
The important and novel finding of this study is that modest fat gain in normal-weight healthy young subjects under standardized conditions of diet and activity is associated with attenuated endothelial function, even in the absence of changes in blood pressure. Endothelial function recovers after reversal of the fat gain. Importantly, endothelial dysfunction is significantly linked to visceral but not to subcutaneous fat gain.
To our knowledge, this is the first randomized controlled longitudinal study to demonstrate that in normal-weight healthy young subjects, modest visceral fat gain is associated with blunted FMD. Endothelial dysfunction is considered an early marker of atherosclerotic disease, with important clinical implications (1,4,10–12). We found that FMD was blunted after weight gain and recovered after the restoration of normal weight, suggesting that changes in endothelial function are reversible, at least in the short term. Moreover, our data suggest that the development of endothelial dysfunction precedes any blood pressure increase.
Interestingly, the magnitude of attenuation in endothelial function in healthy subjects, who gained mainly visceral fat, is very similar to that observed with smoking, diabetes, and aging (13,14). Modest short-term weight gain is often an accepted consequence of the holiday season. Our study provides evidence that modest fat gain affects endothelial function, arguing against our cultural permissiveness toward weight gain or “going up a clothing size” as a “normal” phenomenon and strengthens the case for weight control as a means of attenuating cardiovascular risk.
The selective interaction between endothelial dysfunction and visceral fat gain observed is consistent with epidemiologic studies linking cardiovascular risk to central measures of obesity (15,16). Mechanisms linking visceral adiposity to increased risk include higher levels of adipokines and proinflammatory molecules (17,18). Moreover, free fatty acid flux of visceral fat is biochemically distinct and may be more deleterious to the liver, predisposing to insulin resistance (18) and perhaps endothelial dysfunction. Previous studies have shown an association between adiponectin and endothelial function (19,20). However, in our study population, FMD was not associated with changes in leptin, adiponectin, and CRP, which is in accordance with a recent study that did not find a significant association between FMD and adiponectin levels in obese subjects (21).
Potential limitations of the study include that the intentional weight gain may not fully reflect the long-term gradual changes occurring in uncontrolled conditions in the general population, suggesting some caution in interpreting the results.
Modest fat gain causes endothelial dysfunction in normal-weight, healthy young adults, even in the absence of changes in blood pressure and heart rate. Endothelial function recovers after the reversal of fat gain. Visceral fat gain is significantly correlated with impaired FMD. Endothelial dysfunction secondary to visceral fat gain may be an important mechanism linking central obesity to increased cardiovascular morbidity and mortality.
The authors thank Ms. Debra L. Pfeifer and Ms. Ann B. Peterson for their superb secretarial and administrative assistance, and the expertise of the Clinical Research Unit Nutrition Research team, especially Ms. Kim L. Edens and Ms. Sunita Nayar.
Continuing Medical Education (CME) is available for this article.
Dr. Romero-Corral was supported by a postdoctoral fellowship from the American Heart Association (Dallas, Texas). Dr. Sert-Kuniyoshi was supported by grant 09-20069G from the American Heart Association. Dr. Sierra-Johnson was partially supported by faculty funds from the Board of Post-Graduate Education of Karolinska Institutet (KID Award) and by the European Foundation for the Study of Diabetes (Düsseldorf, Germany) through a research fellowship, and is an employee of Eli Lilly Company. Dr. Singh was supported by grant 0725787Z from the American Heart Association. Dr. Lopez-Jimenez is a recipient of a Clinical Scientist Development Award from the American Heart Association. Dr. Somers was supported by grants R01 HL73211 and R21 DK81014 from the National Institutes of Health (Bethesda, Maryland) and is working with Mayo Health Solutions on intellectual property related to obesity and cardiovascular disease. Drs. Romero-Corral, Lopez-Jimenez, and Somers are recipients of a grant from Select Research (Suckley, United Kingdom) for separate work related to the measurement of obesity. Drs. Orban, Gami, Pusalavidyasagar, Votruba, and Jensen and Ms. Davison and Huyber report that they have no relationships to disclose.
- Abbreviations and Acronyms
- body mass index
- C-reactive protein
- flow-mediated dilation
- Received December 16, 2009.
- Revision received February 22, 2010.
- Accepted March 9, 2010.
- American College of Cardiology Foundation
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