If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
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.
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,
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,
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,
In addition, visceral adiposity has been showed to perform better than other anthropometric measures as a predictor of cardiovascular and all-cause deaths.
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,
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.
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.
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,
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.
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
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.
P<.05 for within-group comparisons as determined from Wilcoxon signed-rank tests.
1662 (−19 to 3343)
7508±2076
8009±2024
501 (−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
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).
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.
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.
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,
Correlation of office and ambulatory blood pressure measurements with urinary albumin and N-acetyl-βD-glucosaminidase excretions in essential hypertension.
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
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.
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,
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,
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.
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,
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
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.
Another mechanism potentially responsible for the observed effects involves overfeeding-induced upregulation of the hypothalamic-pituitary-adrenal axis, which may mediate both BP elevation
Enhanced cortisol production rates, free cortisol, and 11β-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss.
Am J Physiol Endocrinol Metab.2009; 296: E351-E357
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.
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.
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.
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.
Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.
Correlation of office and ambulatory blood pressure measurements with urinary albumin and N-acetyl-βD-glucosaminidase excretions in essential hypertension.
Twenty-four-hour ambulatory blood pressure and duration of hypertension as major determinants for intima-media thickness and atherosclerosis of carotid arteries.
Enhanced cortisol production rates, free cortisol, and 11β-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss.
Am J Physiol Endocrinol Metab.2009; 296: E351-E357
Grant Support: The work was supported by grants RO1 HL73211, R21 DK81014, RO1 HL065176, RO1 HL114024, RO1 HL114676, RO1 HL134808, and RO1 HL134885 (V.K.S.) from the National Institutes of Health (NIH); grant 16SDG27250156 (N.C.) from the American Heart Association; and CCaTS Early Stage Investigator Award (P.S.). This publication was made possible by the Mayo Clinic Center for Clinical and Translational Science through grant UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the NIH.
Potential Competing Interests: Dr Sert-Kuniyoshi is a full-time employee of Philips Respironics. Dr Somers served as a consultant for Respicardia, ResMed, Sorin, Inc, U-Health, Philips, Ronda Grey, and Glaxo Smith Kline and is working with Mayo Health Solutions and their industry partners on intellectual property related to sleep and cardiovascular disease. The rest of the authors report no relevant conflicts of interest.
Data Previously Presented: This work was previously presented in Abstract form at the High Blood Pressure Research 2014 Scientific Sessions of the American Heart Association (Hypertension. 2014;64:A029).
30889-3&id=gr1.jpg){kind=link}