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Experimental Weight Gain Increases Ambulatory Blood Pressure in Healthy Subjects: Implications of Visceral Fat Accumulation

      Abstract

      Objective

      To examine whether experimentally induced weight gain raises ambulatory blood pressure (BP) in healthy subjects and identify any relationship between changes in BP and changes in regional fat distribution.

      Patients and Methods

      Twenty-six normal weight subjects were randomized to 8 weeks of weight gain through overfeeding (n=16; age, 30.4±6.6 years) or to weight maintenance (controls; n=10; age, 27.1±7.7 years) between July 2004 and August 2010. Measures of body composition via dual energy X-ray absorptiometry and computed tomography, circulating biomarkers, and 24-hour ambulatory BP were obtained at baseline and after the 8-week experimental phase.

      Results

      Overfeeding resulted in 3.7 kg (95% CI, 2.9-4.5) increase in body weight in weight gainers, with increments in total (46.2 cm2; 95% CI, 27.6-64.9), visceral (13.8 cm2; 95% CI, 5.8-21.9), and subcutaneous fat (32.4 cm2; 95% CI, 13.5-51.3). No changes occurred in the maintenance group. Increases in 24-hour systolic BP (4 mm Hg; 95% CI, 1.6-6.3), mean BP (1.7 mm Hg; 95% CI, 0.3-3.3), and pulse pressure (2.8 mm Hg; 95% CI, 1.1-4.4) were evident after weight gain in the experimental group, whereas BP remained unchanged in controls. Changes in mean BP correlated only with changes in visceral fat (ρ=0.45; P=.02), but not with changes in other body composition measures.

      Conclusion

      Modest weight gain causes elevation in 24-hour BP in healthy subjects. The association between increased BP and abdominal visceral fat accumulation suggests that visceral deposition of adipose tissue may contribute specifically to the enhanced risk of hypertension associated with weight gain.

      Abbreviations and Acronyms:

      BMI (body mass index), BP (blood pressure), DBP (diastolic blood pressure), HR (heart rate), MAP (mean arterial pressure), PP (pulse pressure), RAS (renin-angiotensin system), SBP (systolic blood pressure)
      Excess body weight is widely recognized as a leading contributor to morbidity and mortality,
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      Impact of overweight on the risk of developing common chronic diseases during a 10-year period.
      being associated with enhanced vulnerability to various cardiovascular and noncardiovascular diseases including hypertension. Current estimates on the prevalence of hypertension show that 36% to 47% of the obese population suffers from high blood pressure (BP), compared with 20% of normal weight individuals,
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      and prospective studies have consistently identified increased body weight as a determinant of BP elevation and new-onset hypertension.
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      Change in body mass index and its impact on blood pressure: a prospective population study.
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      • et al.
      Associations between weight gain and incident hypertension in a bi-ethnic cohort: the Atherosclerosis Risk in Communities Study.
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      • et al.
      Body mass index and risk of incident hypertension over the life course: the Johns Hopkins Precursors Study.
      Nevertheless, there is substantial variability in the disease risk conferred by excess weight when individuals are stratified solely on the basis of their body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared). In spite of its conventional use as a surrogate for total body adiposity, BMI does not discriminate between lean mass and fat mass, nor does it take into account fat partitioning among various depots. In this regard, growing evidence indicates that the anatomic location of fat accumulation is a key feature in determining risk status,
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      suggesting that interindividual differences in disease propensity may be partially ascribed to the heterogeneity in regional adiposity distribution existing at any given BMI. Specifically, abdominal visceral obesity has recently emerged as the obesity-phenotype conveying the most unfavorable health profile.
      In comparison to total and subcutaneous adiposity, visceral fat is more closely related to cardiometabolic risk factors, such as fasting glucose, lipids, and endothelial function,
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      Visceral and subcutaneous adiposity and brachial artery vasodilator function.
      as well as to the presence of overt diseases such as coronary atherosclerosis and stroke.
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      • et al.
      Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study.
      In addition, visceral adiposity has been showed to perform better than other anthropometric measures as a predictor of cardiovascular and all-cause deaths.
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      Body fat distribution, incident cardiovascular disease, cancer, and all-cause mortality.
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      • Ross R.
      Visceral fat is an independent predictor of all-cause mortality in men.
      The critical role of visceral fat in obesity-related hypertension is increasingly apparent. Several population-based studies, including the Framingham and the Jackson cohorts, have linked visceral fat deposition to heightened BP values and greater prevalence of hypertension,
      • Fox C.S.
      • Massaro J.M.
      • Hoffmann U.
      • et al.
      Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study.
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      • Fox C.S.
      • Hickson D.A.
      • et al.
      Impact of abdominal visceral and subcutaneous adipose tissue on cardiometabolic risk factors: the Jackson Heart Study.
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      • Jeppesen J.L.
      Abdominal adiposity distribution quantified by ultrasound imaging and incident hypertension in a general population.
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      • Leonetti D.L.
      • et al.
      Visceral adiposity and the prevalence of hypertension in Japanese Americans.
      with these associations being independent of total body weight and subcutaneous adiposity. More recently, observational longitudinal data on the impact of visceral fat accumulation on incident hypertension have also been reported.
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      • Thuesen B.H.
      • Linneberg A.
      • Jeppesen J.L.
      Abdominal adiposity distribution quantified by ultrasound imaging and incident hypertension in a general population.
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      • et al.
      The relationship of body mass and fat distribution with incident hypertension: observations from the Dallas Heart Study.
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      • Boyko E.J.
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      • Boyko E.J.
      • Leonetti D.L.
      • et al.
      Visceral adiposity is an independent predictor of incident hypertension in Japanese Americans.
      Nevertheless, unlike the relative abundancy of observational evidence connecting visceral fat deposition to high BP, there is a paucity of interventional, mechanistic studies addressing the effects of experimental fat gain, and specifically of increases in visceral fat, on BP in human subjects.
      Building upon these considerations, we conducted a randomized controlled study to examine whether experimental weight gain raises 24-hour ambulatory BP in healthy individuals (primary outcome) and to define the relative contribution of changes in regional fat distribution (secondary outcome). We hypothesized that overfeeding-induced weight gain would increase ambulatory BP and that fat deposition in the visceral compartment would be preferentially associated with larger BP increments.

      Patients and Methods

      Study Population

      Twenty-six nonobese, healthy individuals (16 males; mean ± SD age, 29.1±7.1 years; BMI, 23.6±3.1 kg/m2) were recruited as part of a larger project on the effects of weight gain on cardiometabolic health.
      • Adachi T.
      • Sert-Kuniyoshi F.H.
      • Calvin A.D.
      • et al.
      Effect of weight gain on cardiac autonomic control during wakefulness and sleep.
      • Romero-Corral A.
      • Sert-Kuniyoshi F.H.
      • Sierra-Johnson J.
      • et al.
      Modest visceral fat gain causes endothelial dysfunction in healthy humans.
      • Singh P.
      • Somers V.K.
      • Romero-Corral A.
      • et al.
      Effects of weight gain and weight loss on regional fat distribution.
      Eligible subjects had to be sedentary, nonsmokers, free of overt medical or psychiatric diseases, and not taking any medications aside from the birth control pill for women. Absence of undiagnosed medical conditions was confirmed by physical examination, collection of medical history, and polysomnography to rule out sleep disordered breathing. A negative pregnancy test result was required for women.
      The protocol was approved by the Mayo Clinic Institutional Review Board and informed consent was obtained from all participants. These studies were conducted between July 1, 2004, and August 31, 2010.

      Study Design

      Subjects underwent an initial 3-day period of weight maintenance, during which they adhered to a dietary regimen consisting of 40% carbohydrate, 40% fat, and 20% protein. The individual calorie intake required for weight stability was determined by research dieticians after consultation with each participant.
      Following baseline evaluation, enrolled subjects were randomized to an 8-week experimental protocol of either moderate weight gain (5% increase in body weight) or weight maintenance. Subjects assigned to the weight gain group (n=16) were instructed to increase their habitual food intake by increasing their portion sizes or by consuming 400 to 1200 extra kcal/d via dietary supplements. Available supplements were chocolate bars (king-size Snickers bar, 510 kcal; Mars Inc), ice-cream shakes (402 kcal), and nutritional energy drinks (Boost Plus, 360 kcal/8 oz; Nestle Nutrition). Participants randomized to weight maintenance (n=10) were instructed to continue with their normal diet for the 8-week experimental phase. Weight measures were obtained 5 times/wk or more during the study and caloric intakes were adjusted to achieve the targeted increase in body weight in gainers. Adherence to usual diet was reinforced in maintainers if they exhibited ±2% changes in body weight. All subjects were advised to maintain their usual lifestyle routines throughout the study period with the exception of avoiding caffeine and alcohol consumption for 24-hour before and on the day scheduled for measurements. Body composition, BP, and blood specimen measures were taken at study entry and after completion of the 8-week experimental protocol.

      Measures

      Body Composition Measures

      Height and weight were measured by an electronic scale and a stadiometer, respectively, and BMI was calculated. Waist and hip circumferences were measured by nonelastic tape.
      Whole-body dual energy X-ray absorptiometry (DPX-IQ, Lunar Radiation) was used to obtain total body fat mass and fat-free mass.
      Single-slice abdominal computed tomographic scans were collected at 3 intervertebral spaces (L2-3, L3-4 and L4-5). Total, visceral, and subcutaneous fat areas were quantified by a blinded, trained observer as described elsewhere,
      • Potretzke A.M.
      • Schmitz K.H.
      • Jensen M.D.
      Preventing overestimation of pixels in computed tomography assessment of visceral fat.
      and the average values from the 3 slices were derived.

      BP Measures

      Resting supine systolic and diastolic BP (SBP/DBP) measurements were obtained using an automatic sphygmomanometer (Dinamap 8100, Critikon). Ambulatory BP monitors (Spacelabs 90207; Spacelabs Medical, Inc) with cuffs of appropriate size were fitted to each subject's arm. Readings were taken at 30-minute intervals during the day and every 60 minutes at night (10 pm to 6 am). Participants were instructed to fill out a diary to record their activity when wearing the monitors. Artefactual readings were removed according to the manufacturer's setting.
      Twenty-four-hour averages were computed for SBP, DBP, mean BP (mean arterial pressure [MAP], mm Hg), pulse pressure (PP, mm Hg), and heart rate (HR, bpm). Mean daytime and nighttime values were estimated on the basis of diary entries. Blood pressure variability was estimated as SD of SBP and DBP for each 24-hour period.

      Biochemical Measures

      Fasting morning blood samples for determination of lipid profile (high-density lipoprotein, low-density lipoprotein, total cholesterol, triglycerides), insulin, glucose, high-sensitivity C-reactive protein, leptin, and adiponectin were collected and processed as previously reported.
      • Romero-Corral A.
      • Sert-Kuniyoshi F.H.
      • Sierra-Johnson J.
      • et al.
      Modest visceral fat gain causes endothelial dysfunction in healthy humans.

      Statistical Analyses

      Data are presented as counts for categorical variables and means ± SD for continuous variables. Changes from baseline to follow-up are expressed as means (95% CI). Because of limited sample size and unmet assumptions for general linear models, nonparametric tests were applied. Subject characteristics at study entry were compared by group using Wilcoxon rank-sum and chi-square tests when appropriate. Wilcoxon signed-rank tests were applied to assess changes from baseline. To identify body composition parameters related to variations in BP, we ran Spearman rank correlations on the pooled sample. Multivariable regression models were also explored to assess independence of observed associations. JMP Pro 9.0 (SAS Institute Inc) was used for statistical analyses, with the significance level set a priori at P<.05.

      Results

      Subject characteristics at study entry and at follow-up are listed in Table 1. Baseline demographic, anthropometric, and body composition measures were comparable between groups. Glucose was higher in weight gainers, whereas C-reactive protein was higher in weight maintainers (both P=.03) at study entry. There were no other group differences in baseline laboratory measures.
      Table 1Patient Characteristics at Baseline and After the 8-Week Experimental Phase
      BMI = body mass index; HDL = high-density lipoprotein; hs-CRP = high-sensitivity C-reactive protein; LDL = low-density lipoprotein.
      ,
      Values are mean ± SD and counts. Changes from baseline to follow-up are expressed as mean (95% CI).
      ,
      SI conversion factors: To convert insulin to pmol/L, multiply by 6.945; to convert glucose to mmol/L, multiply by .0555; to convert total cholesterol, HDL, and LDL to mmol/L, multiply by .0259; to convert triglycerides to mmol/L, multiply by .0113; to convert leptin to μg/L, multiply by 1.0; to convert adiponectin to μg/mL, multiply by .001.
      CharacteristicWeight gainers (n=16)Controls (n=10)
      BaselineWeight gainChange (95% CI)BaselineWeight maintenanceChange (95% CI)
      Age (y)30.4±6.627.1±7.7
      Sex: male, n106
      Weight (kg)71.9±12.975.6±13.4
      P<.001 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      3.7 (2.9 to 4.5)74.2±16.574.3±16.10.1 (−0.6 to 0.8)
      BMI (kg/m2)23.5±3.524.8±3.6
      P<.001 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      1.3 (0.9 to 1.5)23.6±2.723.7±2.60.1 (−0.2 to 0.3)
      Waist circumference (cm)84.9±9.488.5±9.7
      P<.001 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      3.6 (1.9 to 5.2)80.1±10.880.6±11.10.5 (−0.1 to 1.1)
      Hip circumference (cm)98.5±6.2101.1±6.5
      P<.01 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      2.6 (1.3 to 4)98.6±7.898.8±7.70.2 (−1.5 to 1.7)
      Total body fat mass (kg)21.9±8.225.2±8.6
      P<.001 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      3.3 (1.9 to 4.4)20.4±6.721±6.70.6 (0 to 1.1)
      Total body fat-free mass (kg)46.9±9.347.3±9.60.4 (−0.4 to 1.3)50.6±12.150.2±12−0.4 (−1.4 to 0.5)
      % Body fat31.5±8.934.4±8.7
      P<.001 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      2.9 (1.4 to 4.3)28.7±6.729.4±6.60.7 (−0.1 to 1.5)
      Abdominal total fat area (cm2)197.1±99.3243.3±105
      P<.001 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      46.2 (27.6 to 64.9)171.8±77.5176±76.34.2 (−9.5 to 17.8)
      Abdominal visceral fat area (cm2)61.6±32.775.5±30.9
      P<.01 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      13.9 (5.8 to 21.9)46.6±34.247.2±35.70.6 (−6.5 to 7.7)
      Abdominal subcutaneous fat area (cm2)135.5±77.4167.9±82.9
      P<.001 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      32.4 (13.5 to 51.3)125.2±53.1128.7±52.33.5 (−5.1 to 12.1)
      Insulin (U/mL)5.2±2.66.6±3.11.4 (−0.7 to 3.4)5.5±3.64.9±2.6−0.6 (−1.9 to 0.8)
      Glucose (mg/dL)93.5±4.998.9±10.45.4 (−1.1 to 11.8)85.8±6.4
      P<.05 for between-group comparisons as determined from Wilcoxon rank-sum tests.
      87.3±3.81.5 (−4.4 to 7.4)
      Total cholesterol (mg/dL)162.9±20.7163.1±35.30.2 (−15.9 to 16.5)166.8±17.9164.8±13.6−2 (−15.8 to 11.8)
      HDL (mg/dL)45.1±15.545±9.5−0.1 (−8.6 to 8.5)43.9±8.343.1±7.2−0.8 (−6.2 to 4.8)
      LDL (mg/dL)102.4±19.4101.6±29.7−0.8 (−14 to 12.5)106.9±13.5106.6±9.9−0.3 (−8.1 to 7.6)
      Triglycerides (mg/dL)77.1±28.886±46.58.9 (−11.4 to 29.3)80.8±22.869.1±5.9−11.7 (−37.5 to 14.1)
      hs-CRP (mg/L)0.04±0.030.3±0.70.3 (−0.1 to 0.7)0.3±0.6
      P<.05 for between-group comparisons as determined from Wilcoxon rank-sum tests.
      0.07±0.04−0.2 (−0.9 to 0.4)
      Leptin (ng/mL)7.3±4.611.7±5.9
      P<.001 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      4.4 (2.6 to 6.3)5.6±36.9±4.51.3 (−0.7 to 3.3)
      Adiponectin (ng/mL)7324±38748986±5463
      P<.05 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      1662 (−19 to 3343)7508±20768009±2024501 (−492 to 1495)
      a BMI = body mass index; HDL = high-density lipoprotein; hs-CRP = high-sensitivity C-reactive protein; LDL = low-density lipoprotein.
      b Values are mean ± SD and counts. Changes from baseline to follow-up are expressed as mean (95% CI).
      c SI conversion factors: To convert insulin to pmol/L, multiply by 6.945; to convert glucose to mmol/L, multiply by .0555; to convert total cholesterol, HDL, and LDL to mmol/L, multiply by .0259; to convert triglycerides to mmol/L, multiply by .0113; to convert leptin to μg/L, multiply by 1.0; to convert adiponectin to μg/mL, multiply by .001.
      d P<.001 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      e P<.01 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      f P<.05 for between-group comparisons as determined from Wilcoxon rank-sum tests.
      g P<.05 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      As per study design, body weight increased by 3.7 kg (95% CI, 2.9-4.5) in weight gainers after 8 weeks of overfeeding (P<.001), whereas it remained unchanged in maintainers (P=.79). Waist (P=.001) and hip circumferences (P=.002) increased in weight gainers in response to excess calorie consumption.
      Analysis of imaging body composition measures showed that in the experimental group weight gain occurred through increments in fat mass (P<.001), because the fat-free mass did not vary (P=.40). Both subcutaneous (P<.001) and visceral fat areas (P=.003) increased in weight gainers, leading to enlarged total abdominal fat area following overfeeding (P<.001). All body composition metrics were stable in subjects assigned to weight maintenance (all P>.23).
      Insulin and lipid profile did not change appreciably after the dietary intervention (all P>.24), whereas leptin (P<.001) and adiponectin (P=.03) were significantly elevated as compared with baseline in weight gainers. No other changes were seen in either group.
      Blood pressure measures are summarized in Table 2. Office measurements of BP and HR did not vary significantly after the 8-week experimental phase in either the experimental group or the control group. However, increases in 24-hour SBP (P=.009), 24-hour MAP (P=.02), and 24-hour PP (P=.003) were evident after weight gain. No significant changes occurred in 24-hour DBP (P=.10) or 24-hour HR (P=.53) after weight gain.
      Table 2BP Variables at Baseline and After the 8-Week Experimental Phase
      BP = blood pressure; DBP = diastolic blood pressure; HR = heart rate; MAP = mean arterial pressure; PP = pulse pressure; SBP = systolic blood pressure.
      ,
      Values are mean ± SD. Changes from baseline to follow-up are expressed as mean (95% CI).
      BP variableWeight gainers (n=16)Controls (n=10)
      BaselineWeight gainChange (95% CI)BaselineWeight maintenanceChange (95% CI)
      Office BP (mm Hg)
       Office SBP115.9±12.3117.6±15.31.7 (−6.5 to 9.8)113.4±9.8114.8±7.81.4 (−4.6 to 7.4)
       Office DBP73.6±11.670.6±11.1−3 (−9.5 to 3.6)68.3±5.469.6±9.41.3 (−6.6 to 9.2)
       Office HR (bpm)65±8.866.8±8.21.8 (−3 to 6.5)67.5±15.366.1±12.9−1.4 (−6.1 to 3.3)
      24-hour BP (mm Hg)
       SBP113.7±8117.7±7.9
      P<.01 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      4 (1.6 to 6.3)115.6±7116±70.4 (−2.5 to 3.4)
       DBP70.7±4.371.9±4.41.2 (−0.2 to 2.6)68.6±3.768.9±4.30.3 (−1.9 to 2.7)
       MAP85.1±4.986.8±5.1
      P<.05 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      1.7 (0.3 to 3.3)84.1±2.984.4±3.50.3 (−1.9 to 2.6)
       PP43±545.8±5
      P<.01 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      2.8 (1.1 to 4.4)47±7.747.1±7.70.1 (−1.5 to 1.6)
       HR (bpm)71±8.872±7.81 (−2.9 to 5)69.8±9.272.7±9.3
      P<.05 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      2.9 (0.9 to 5)
      Daytime BP (mm Hg)
       SBP117.7±8.4121.5±8.9
      P<.01 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      3.8 (1.3 to 6.2)118±7.2118.7±6.90.7 (−1.9 to 3.4)
       DBP74.4±4.575.6±51.2 (−0.1 to 2.4)71.3±3.771.7±4.70.4 (−2.2 to 3)
       MAP88.7±5.290.4±5.9
      P<.05 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      1.7 (0.3 to 3)86.7±3.187.3±3.80.6 (−1.8 to 3)
       PP43.3±5.245.9±5.3
      P<.01 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      2.6 (0.7 to 4.6)46.7±8.147±7.60.3 (−1.1 to 1.9)
       HR (bpm)74.3±9.774.8±8.10.5 (−3.9 to 4.9)71.9±9.775.9±9.5
      P<.01 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      4 (1.6 to 6.4)
      Nighttime BP (mm Hg)
       SBP100.9±7105.8±6.6
      P<.05 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      4.9 (1.3 to 8.6)106.6±8.2106.7±90.1 (−5.8 to 6)
       DBP58.3±4.559.7±5.11.4 (−1.4 to 4.3)58.1±4.859.7±4.51.6 (−1 to 4.1)
       MAP73.1±4.575.3±4.82.2 (−0.7 to 5.2)74.4±4.375±4.30.6 (−2.9 to 4.1)
       PP42.6±5.546.1±6
      P<.05 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      3.5 (0.8 to 6.3)48.5±8.147.1±7.9−1.4 (−5.1 to 2.3)
       HR (bpm)60.4±762.8±8.42.4 (−1.8 to 6.6)61.2±8.962±10.30.8 (−2.7 to 4.2)
      BP Variability (mm Hg)
       SBP11.4±2.411.1±3.1−0.3 (−1.6 to 1.1)10.1±211.5±2.81.4 (−0.7 to 3.4)
       DBP10.7±1.910.7±1.80 (−1 to 1.1)10.1±2.210.4±2.30.3 (−1.3 to 2)
      a BP = blood pressure; DBP = diastolic blood pressure; HR = heart rate; MAP = mean arterial pressure; PP = pulse pressure; SBP = systolic blood pressure.
      b Values are mean ± SD. Changes from baseline to follow-up are expressed as mean (95% CI).
      c P<.01 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      d P<.05 for within-group comparisons as determined from Wilcoxon signed-rank tests.
      Evaluation of the diurnal profile showed that SBP was higher during both daytime (P=.009) and nighttime (P=.01) in weight gainers after overfeeding. A similar pattern was seen in PP, which was higher in both the daytime (P=.009) and nighttime (P=.02), whereas MAP was significantly more elevated during daytime only (P=.03). There were no significant changes in daytime and nighttime readings of DBP and HR (all P>.12). Ambulatory BP measures remained unchanged in weight maintainers (all P>.13), but they exhibited higher 24-hour (P=.01) and daytime HR (P=.002) at follow-up. Blood pressure variability was stable in both groups (all P>.19).
      Spearman rank correlations run on the pooled sample showed that the magnitude of changes in MAP was significantly related to the magnitude of changes in abdominal visceral fat (ρ=0.45; P=.02) (Figure A ). Elevation in MAP was not related to increases in body weight (ρ=0.16; P=.43; Figure B) or waist circumference (ρ=0.2; P=.38; Figure C). No associations were seen with total body fat (ρ=0.02, P=.92) or subcutaneous body fat (ρ=0.16, P=.44) either. Changes in visceral fat remained significantly associated with changes in BP even when controlling for weight gain (R2=0.21, P=.03; visceral fat estimate=0.1, P=.03), and when controlling for changes in total adiposity (R2=0.29, P=.02; visceral fat estimate=0.13, P=.005). None of these variables was associated with increases in BP (weight estimate=−0.1, P=.73; total adiposity estimate=−0.0005, P=.1).
      Figure thumbnail gr1
      FigureRelation between changes in MAP and changes in abdominal visceral fat (A), weight (B), and waist circumference (C) in the pooled sample (N=26). MAP = mean arterial pressure.

      Discussion

      Our data show that the exposure of lean, healthy individuals to short-term, overfeeding-induced modest weight gain caused significant elevation in 24-hour ambulatory BP, and that this pressor response was selectively associated with visceral fat expansion. This is the first randomized controlled study of experimental weight gain in humans to demonstrate the role of visceral fat in contributing to increased 24-hour mean BP, independently of generalized weight gain or fat accumulation.
      Twenty-four hour SBP, MAP, and PP increased after 8 weeks of excess calorie intake, whereas neither DBP nor HR varied significantly. The increments in ambulatory SBP and PP observed after 5% weight gain occurred during both daytime and nighttime, whereas MAP was significantly higher during daytime. Notably, the average magnitude of elevation we recorded, while modest, is prognostically significant, because a 2-mm Hg increase in SBP is associated with 7% risk of ischemic heart disease and 10% risk of stroke on a population level.
      • Lewington S.
      • Clarke R.
      • Qizilbash N.
      • Peto R.
      • Collins R.
      Prospective Studies Collaboration
      Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.
      It is now established that ambulatory BP outperforms standard office measures, with compelling evidence attesting to its clinical and prognostic significance. Twenty-four hour BP predicts fatal and nonfatal cardiovascular events independent of conventional covariates including office BP,
      • Staessen J.A.
      • Thijs L.
      • Fagard R.
      • et al.
      Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension.
      • Kikuya M.
      • Ohkubo T.
      • Asayama K.
      • et al.
      Ambulatory blood pressure and 10-year risk of cardiovascular and noncardiovascular mortality.
      • Dolan E.
      • Stanton A.
      • Thijs L.
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      Superiority of ambulatory over clinic blood pressure measurement in predicting mortality.
      and correlates more closely with target organ damage than do clinic readings.
      • Benhamou P.Y.
      • Halimi S.
      • De Gaudemaris R.
      • et al.
      Early disturbances of ambulatory blood pressure load in normotensive type I diabetic patients with microalbuminuria.
      • Opsahl J.A.
      • Abraham P.A.
      • Halstenson C.E.
      • Keane W.F.
      Correlation of office and ambulatory blood pressure measurements with urinary albumin and N-acetyl-βD-glucosaminidase excretions in essential hypertension.
      • Su T.C.
      • Lee Y.T.
      • Chou S.
      • Hwang W.T.
      • Chen C.F.
      • Wang J.D.
      Twenty-four-hour ambulatory blood pressure and duration of hypertension as major determinants for intima-media thickness and atherosclerosis of carotid arteries.
      In addition, by delineating the BP patterning over the 24-hour period, ambulatory BP monitoring enables characterization of daytime versus nighttime BP separately. In this regard, the predictive power of nighttime BP exceeds that of office and even 24-hour BP for subclinical organic injury
      • Benhamou P.Y.
      • Halimi S.
      • De Gaudemaris R.
      • et al.
      Early disturbances of ambulatory blood pressure load in normotensive type I diabetic patients with microalbuminuria.
      • Cuspidi C.
      • Facchetti R.
      • Bombelli M.
      • et al.
      Nighttime blood pressure and new-onset left ventricular hypertrophy: findings from the Pamela population.
      and adverse cardiovascular outcomes including cardiovascular mortality,
      • Staessen J.A.
      • Thijs L.
      • Fagard R.
      • et al.
      Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension.
      • Kikuya M.
      • Ohkubo T.
      • Asayama K.
      • et al.
      Ambulatory blood pressure and 10-year risk of cardiovascular and noncardiovascular mortality.
      • Dolan E.
      • Stanton A.
      • Thijs L.
      • et al.
      Superiority of ambulatory over clinic blood pressure measurement in predicting mortality.
      thus further supporting the superiority of BP measures derived from ambulatory BP monitoring.
      Previous investigations using similar experimental approaches have examined the impact of overfeeding-induced weight gain on BP,
      • Gentile C.L.
      • Orr J.S.
      • Davy B.M.
      • Davy K.P.
      Cardiorespiratory fitness influences the blood pressure response to experimental weight gain.
      • Gentile C.L.
      • Orr J.S.
      • Davy B.M.
      • Davy K.P.
      Modest weight gain is associated with sympathetic neural activation in nonobese humans.
      • Gupta A.K.
      • Johnson W.D.
      • Johannsen D.
      • Ravussin E.
      Cardiovascular risk escalation with caloric excess: a prospective demonstration of the mechanics in healthy adults.
      • Orr J.S.
      • Gentile C.L.
      • Davy B.M.
      • Davy K.P.
      Large artery stiffening with weight gain in humans: role of visceral fat accumulation.
      although only a few of them included ambulatory recordings.
      • Gentile C.L.
      • Orr J.S.
      • Davy B.M.
      • Davy K.P.
      Cardiorespiratory fitness influences the blood pressure response to experimental weight gain.
      • Orr J.S.
      • Gentile C.L.
      • Davy B.M.
      • Davy K.P.
      Large artery stiffening with weight gain in humans: role of visceral fat accumulation.
      Gentile et al
      • Gentile C.L.
      • Orr J.S.
      • Davy B.M.
      • Davy K.P.
      Modest weight gain is associated with sympathetic neural activation in nonobese humans.
      reported higher ambulatory and office BP after a 5-kg increment in body weight, whereas Gupta et al
      • Gupta A.K.
      • Johnson W.D.
      • Johannsen D.
      • Ravussin E.
      Cardiovascular risk escalation with caloric excess: a prospective demonstration of the mechanics in healthy adults.
      found that 5% to 10% weight gain raised 24-hour ambulatory BP in absence of significant variations in resting measurements. Importantly, these studies lacked a control group of weight maintainers, and the increased body weight resulted from increments in both fat mass and fat-free mass.
      • Gentile C.L.
      • Orr J.S.
      • Davy B.M.
      • Davy K.P.
      Cardiorespiratory fitness influences the blood pressure response to experimental weight gain.
      • Gentile C.L.
      • Orr J.S.
      • Davy B.M.
      • Davy K.P.
      Modest weight gain is associated with sympathetic neural activation in nonobese humans.
      • Gupta A.K.
      • Johnson W.D.
      • Johannsen D.
      • Ravussin E.
      Cardiovascular risk escalation with caloric excess: a prospective demonstration of the mechanics in healthy adults.
      • Orr J.S.
      • Gentile C.L.
      • Davy B.M.
      • Davy K.P.
      Large artery stiffening with weight gain in humans: role of visceral fat accumulation.
      In our study higher body weight was achieved through fat accumulation only, because the fat-free mass remained unchanged; therefore, the effects we found can be unequivocally attributed to augmented adiposity.
      The observed increase in the pulsatile component of BP, as reflected by amplification of PP, in combination with heightened SBP (and unchanged DBP), suggests reduced vascular distensibility and compliance in response to overfeeding. When interpreted in the context of our previous findings of impaired endothelial function after moderate weight gain,
      • Romero-Corral A.
      • Sert-Kuniyoshi F.H.
      • Sierra-Johnson J.
      • et al.
      Modest visceral fat gain causes endothelial dysfunction in healthy humans.
      these data are indicative of increased arterial stiffness. Such a hypothesis is consistent with a previous report of higher arterial stiffness and diminished arterial compliance secondary to weight gain,
      • Orr J.S.
      • Gentile C.L.
      • Davy B.M.
      • Davy K.P.
      Large artery stiffening with weight gain in humans: role of visceral fat accumulation.
      and corroborates the idea of early vascular damage induced by fat accumulation.
      Further insights into the mechanisms involved in the pressor response to excess calorie intake arise from the association found between BP increases and expanded visceral adipose tissue depot. Although the pathophysiology of obesity-related hypertension is likely multifactorial, a growing body of research indicates that visceral fat may be a key contributor.
      • Seven E.
      • Thuesen B.H.
      • Linneberg A.
      • Jeppesen J.L.
      Abdominal adiposity distribution quantified by ultrasound imaging and incident hypertension in a general population.
      • Chandra A.
      • Neeland I.J.
      • Berry J.D.
      • et al.
      The relationship of body mass and fat distribution with incident hypertension: observations from the Dallas Heart Study.
      • Sullivan C.A.
      • Kahn S.E.
      • Fujimoto W.Y.
      • Hayashi T.
      • Leonetti D.L.
      • Boyko E.J.
      Change in intra-abdominal fat predicts the risk of hypertension in Japanese Americans.
      • Hayashi T.
      • Boyko E.J.
      • Leonetti D.L.
      • et al.
      Visceral adiposity is an independent predictor of incident hypertension in Japanese Americans.
      Our findings are in line with this construct, as we observed, for the first time, that the elevation in BP after overfeeding was not related to changes in body weight or total body fat but specifically to increases in visceral fat.
      A number of mechanisms have been implicated in the BP surge associated with visceral fat accumulation. Visceral adiposity has been proposed as a link between obesity and sympathetic upregulation,
      • Alvarez G.E.
      • Beske S.D.
      • Ballard T.P.
      • Davy K.P.
      Sympathetic neural activation in visceral obesity.
      • Alvarez G.E.
      • Ballard T.P.
      • Beske S.D.
      • Davy K.P.
      Subcutaneous obesity is not associated with sympathetic neural activation.
      a key mediator of comorbid hypertension in the obese population.
      • Kalil G.Z.
      • Haynes W.G.
      Sympathetic nervous system in obesity-related hypertension: mechanisms and clinical implications.
      • Esler M.
      • Straznicky N.
      • Eikelis N.
      • Masuo K.
      • Lambert G.
      • Lambert E.
      Mechanisms of sympathetic activation in obesity-related hypertension.
      Central sympathetic outflow, as measured from muscle sympathetic nerve activity, is higher in visceral obese than in subcutaneous obese
      • Alvarez G.E.
      • Beske S.D.
      • Ballard T.P.
      • Davy K.P.
      Sympathetic neural activation in visceral obesity.
      and does not differ between subcutaneously obese and nonobese men with similar levels of visceral adiposity.
      • Alvarez G.E.
      • Ballard T.P.
      • Beske S.D.
      • Davy K.P.
      Subcutaneous obesity is not associated with sympathetic neural activation.
      Similarly, cardiac sympathetic activity was found to be higher in visceral obese than in subcutaneous obese,
      • Gao Y.Y.
      • Lovejoy J.C.
      • Sparti A.
      • Bray G.A.
      • Keys L.K.
      • Partington C.
      Autonomic activity assessed by heart rate spectral analysis varies with fat distribution in obese women.
      and more closely related to visceral than to subcutaneous fat depots.
      • Hillebrand S.
      • Mutsert R.
      • Christen T.
      • et al.
      NEO Study Group
      Body fat, especially visceral fat, is associated with electrocardiographic measures of sympathetic activation.
      Because the renin-angiotensin system (RAS) is overexpressed in the visceral compartment,
      • Giacchetti G.
      • Faloia E.
      • Mariniello B.
      • et al.
      Overexpression of the renin-angiotensin system in human visceral adipose tissue in normal and overweight subjects.
      • Dusserre E.
      • Moulin P.
      • Vidal H.
      Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues.
      expansion of this fat depot could elicit angiotensinogen and angiotensin II production, which would then increase BP. Support for this idea arises from previous research showing activation of systemic
      • Gentile C.L.
      • Orr J.S.
      • Davy B.M.
      • Davy K.P.
      Modest weight gain is associated with sympathetic neural activation in nonobese humans.
      and adipose tissue
      • Alligier M.
      • Meugnier E.
      • Debard C.
      • et al.
      Subcutaneous adipose tissue remodeling during the initial phase of weight gain induced by overfeeding in humans.
      RAS in response to overfeeding. However, we cannot exclude the possibility that visceral fat gain does not play a causative role in the BP elevation observed in our study, and a third factor may drive changes in both variables. In this regard, RAS activation secondary to excess calorie consumption, and particularly increased angiotensin II, may both raise BP and favor visceral fat accumulation, as suggested by an in vitro study reporting stimulation of human visceral adipocyte proliferation by angiotensin II.
      • Sarzani R.
      • Marcucci P.
      • Salvi F.
      • et al.
      Angiotensin II stimulates and atrial natriuretic peptide inhibits human visceral adipocyte growth.
      Another mechanism potentially responsible for the observed effects involves overfeeding-induced upregulation of the hypothalamic-pituitary-adrenal axis, which may mediate both BP elevation
      • Grassi G.
      • Seravalle G.
      • Dell'Oro R.
      • et al.
      Participation of the hypothalamus-hypophysis axis in the sympathetic activation of human obesity.
      and predisposition to visceral fat accumulation.
      • Purnell J.Q.
      • Kahn S.E.
      • Samuels M.H.
      • Brandon D.
      • Loriaux D.L.
      • Brunzell J.D.
      Enhanced cortisol production rates, free cortisol, and 11β-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss.
      Further research is needed to directly address these hypotheses.
      Strengths of our work include the application of a randomized, controlled, interventional, longitudinal study design; inclusion of only healthy, nonobese individuals without previous risk factors; and a control group of weight maintainers. Furthermore, to determine body composition, we used criterion standard imaging techniques that yield quantitative and qualitative characterization of body fat compartments. Nonetheless, several limitations have to be recognized, including the modest sample size that precludes us from assessing whether the impact of weight gain varied on the basis of sex or age. The changes in BP we observed occurred in response to a relatively short intervention period and it is plausible that adaptation may occur after prolonged overfeeding and increased body weight. Hence, larger studies and longer periods of follow-up are warranted. Furthermore, our study was not designed to identify the biological mechanisms underlying changes in BP in response to excess calorie intake nor the role of individual macronutrients.
      The early pressor response observed after 5% increase in body weight highlights the detrimental impact of even modest weight gain. Our findings are in accord with previous research documenting that even moderate increments in body weight raise vulnerability to cardiovascular disease, and particularly to hypertension.
      • Juhaeri J.
      • Stevens J.
      • Chambless L.E.
      • et al.
      Associations between weight gain and incident hypertension in a bi-ethnic cohort: the Atherosclerosis Risk in Communities Study.
      • Huang Z.
      • Willett W.C.
      • Manson J.E.
      • et al.
      Body weight, weight change, and risk for hypertension in women.
      • Vasan R.S.
      • Larson M.G.
      • Leip E.P.
      • Kannel W.B.
      • Levy D.
      Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study.
      A longitudinal analysis of the Framingham cohort found that a 5% increment in body weight, which aligns with the magnitude of weight gain sought in our study, was associated with a 20% to 30% enhanced likelihood of future hypertension.
      • Vasan R.S.
      • Larson M.G.
      • Leip E.P.
      • Kannel W.B.
      • Levy D.
      Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study.
      Importantly, the health consequences of modest weight gain are likely exacerbated when fat is primarily accumulated in the abdominal visceral region.
      In terms of preventive and therapeutic strategies for BP management, the antihypertensive effects of weight control are well-established
      • Gay H.C.
      • Rao S.G.
      • Vaccarino V.
      • Ali M.K.
      Effects of different dietary interventions on blood pressure: systematic review and meta-analysis of randomized controlled trials.
      and clinically relevant benefits can be achieved with moderate weight loss.
      • Engeli S.
      • Böhnke J.
      • Gorzelniak K.
      • et al.
      Weight loss and the renin-angiotensin-aldosterone system.
      • Stevens V.J.
      • Obarzanek E.
      • Cook N.R.
      • et al.
      Trials for the Hypertension Prevention Research Group
      Long-term weight loss and changes in blood pressure: results of the Trials of Hypertension Prevention, phase II.
      Mirroring the differential impact of regional fat depots on disease risk, evidence suggests that selective reductions in visceral fat are more effective in improving the cardiometabolic profile, including lowering BP, compared with reduced subcutaneous fat depots and generalized weight loss.
      • Goodpaster B.H.
      • Kelley D.E.
      • Wing R.R.
      • Meier A.
      • Thaete F.L.
      Effects of weight loss on regional fat distribution and insulin sensitivity in obesity.
      • Kanai H.
      • Tokunaga K.
      • Fujioka S.
      • Yamashita S.
      • Kameda-Takemura K.K.
      • Matsuzawa Y.
      Decrease in intra-abdominal visceral fat may reduce blood pressure in obese hypertensive women.
      • Miyatake N.
      • Takahashi K.
      • Wada J.
      • et al.
      Daily exercise lowers blood pressure and reduces visceral adipose tissue areas in overweight Japanese men.
      Therefore, efforts to identify weight loss and weight management interventions preferentially facilitating visceral fat mobilization should be undertaken.

      Conclusion

      Our research found that moderate weight gain in healthy individuals leads to elevation in BP, with the rise in mean BP being selectively related to increases in visceral adipose tissue. These findings have important epidemiological and clinical implications, suggesting that healthy subjects who are predisposed to visceral fat gain are also predisposed to accompanying increases in BP. Therefore, the accumulation of abdominal visceral fat may be a critical determinant in the high risk of hypertension associated with weight gain and obesity. Furthermore, even modest weight gain can contribute to an increase in BP if the fat accumulation is predominantly visceral.

      Supplemental Online Material

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