Circadian Dysregulation, Hypertension, Obesity, Salt; Excess
Conditions
Brief summary
Experimental data have shown that timing of sodium intake impacts diurnal patterns of sodium excretion. The purpose of this study is to test the hypothesis that the time of day for salt intake impacts (1) blood pressure rhythms and urinary sodium excretion and (2) circadian timing of factors responsible for blood pressure regulation and cardiometabolic health in obese individuals. These studies will address two aims. The first aim will test the hypothesis that limiting high salt intake prior to sleep increases day-night differences in blood pressure, improves timing of urinary sodium excretion, and improves metabolic risk factors. The second aim will test the hypothesis that limiting high salt intake prior to sleep preferentially improves rhythmicity in peripheral vs. central circadian clock factors linked to renal sodium handling. The proposed hypothesis-driven studies will determine how timing of sodium intake affects diurnal blood pressure and circadian timing of factors responsible for blood pressure control and metabolic health, with the ultimate goal of identifying novel strategies to treat nocturnal hypertension and metabolic disease in obesity.
Detailed description
Timing of food intake affects a variety of pathophysiological systems. The Western diet, which is high in salt, also contributes to excess morbidity and mortality related to obesity and hypertension. Nocturnal hypertension frequently occurs in obesity and is recognized as an important consequence of hypertension risk, yet the mechanisms involved in this phenomenon are poorly understood. Experimental data from our group have shown that timing of sodium intake impacts diurnal patterns of sodium excretion. Further, we recently reported that high salt intake causes a shift in expression of circadian control genes in the kidney. Additional studies demonstrate that obese animals have an impaired response to a natriuretic stimulus. Given the established contribution of high salt intake to obesity-dependent hypertension, particularly, nocturnal hypertension, we hypothesize that the time of day for salt intake impacts (1) blood pressure rhythms and urinary sodium excretion and (2) circadian timing of factors responsible for blood pressure regulation and cardiometabolic health in obese individuals. We will conduct a cross-over feeding study of 55 obese adults. These studies will address two aims. The first aim will test the hypothesis that limiting high salt intake prior to sleep increases day-night differences in blood pressure, improves timing of urinary sodium excretion, and improves metabolic risk factors. We will monitor 24-hour blood pressure by ambulatory blood pressure monitoring to determine the role of timing of sodium intake on diurnal blood pressure patterns. Day- and night-time sodium excretion will be used to determine whether improvements in blood pressure are mediated by enhanced sodium excretion during the day. We will also assess the effects of timing of sodium intake on lipids, leptin, adiponectin, insulin sensitivity, inflammatory cytokines, and immune cell activation over 24 hours. The second aim will test the hypothesis that limiting high salt intake prior to sleep preferentially improves rhythmicity in peripheral vs. central circadian clock factors linked to renal sodium handling. Circadian measures of plasma cortisol, dim light melatonin onset, and core body temperature (telemetry) will be used to assess the phase and amplitude of the core circadian clock. Circadian measures of peripheral clock genes in buccal cells and peripheral blood monocytes will be used to determine the phase and amplitude of the peripheral clock. The proposed hypothesis-driven studies will determine how timing of sodium intake affects diurnal blood pressure and circadian timing of factors responsible for blood pressure control and metabolic health, with the ultimate goal of identifying novel strategies to treat nocturnal hypertension and metabolic disease in obesity
Interventions
OTHEROral sodium supplementation
Participants will receive dietary sodium supplementation in the form of tablets to be taken either with breakfast or dinner.
Sponsors
University of Alabama at Birmingham
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
25 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* obese (BMI 30-50 kg/m2) * 25-45 years of age
Exclusion criteria
* evidence of kidney disease (eGFR \< 60 ml/min/1.73m2 or abnormal urinalysis) * elevated BP (\>150/90 mmHg \[measured at screening in duplicate after 10min lying recumbent\]) * elevated fasting glucose (\>126 g/dL on screening labs) * severe anemia (hemoglobin \< 8 g/dL for women or \< 9 g/dL for men) * significant psychiatric illness (as assessed by a validated screening form) * past or present drug or alcohol abuse (drug screen) * taking 2 or more BP medications or supplements on a regular basis * alcohol intake more than 2 drinks/day * pregnancy * women taking hormone replacement therapy, or post-menopausal women; * shift worker * sleep disorders (such as sleep apnea assessed by Apnea Link) * major chronic disease (e.g., diabetes, lymphocyte disorders) * history of smoking or use of tobacco products within the past year * use of sleep medications, hypnotics, stimulants, or anti-depressants
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sleep Systolic Blood Pressure | On the 8th day of consuming the standarized diet plus chicken-based broth | Systolic blood pressure measured during sleep by 24-hour ambulatory blood pressure monitor starting on the 8th day of consuming the standarized diet plus chicken-based broth |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 24-hour Urinary Sodium Excretion | On the 9th day of consuming the standarized diet plus chicken-based broth | Urinary sodium excretion measured in study arms by 24-hour urine collection starting on the 9th day of consuming the standarized diet plus chicken-based broth |
| Concentrations of Plasma Melatonin | On the 9th day of consuming the standarized diet plus chicken-based broth | Plasma melatonin concentrations measured in blood samples collected every 2 hours for 24 hours starting on the 9th day of consuming the standarized diet plus chicken-based broth |
| Concentrations of Plasma Cortisol | On the 9th day of consuming the standarized diet plus chicken-based broth | Plasma cortisol concentrations measured in study participants every 2 hours for 24 hours starting on the 9th day of consuming the standarized diet plus chicken-based broth |
| Concentrations of Plasma Endothelin 1 | On the 9th day of consuming the standarized diet plus chicken-based broth | Plasma endothelin 1 concentrations measured every 2 hours for 24 hours starting on the 9th day of consuming the standarized diet plus chicken-based broth |
| Concentrations of Plasma Aldosterone | On the 9th day of consuming the standarized diet plus chicken-based broth | Plasma aldosterone concentrations measured every 2 hours for 24 hours starting on the 9th day of consuming the standarized diet plus chicken-based broth |
| Core Body Temperature | On the 8th day of consuming the standardized diet plus chicken-based broth | Core Body Temperature measured using BodyCap On the 8th day of consuming the standardized diet plus chicken-based broth |
| Timing of Plasma Melatonin Increase Under Dim-light Conditions (Dim-light Melatonin Onset) | On the 9th day of consuming the standardized diet plus chicken-based broth | Timing of melatonin increase based on every 2-hour blood draws during the 24 hour admission on the 9th day of consuming the standardized diet plus chicken-based broth |
| Peripheral Blood Monocyte Clock Gene (CLOCK, Bmal1, per1, per2, Rev-erb-alpha, cry1, cry2) Expression | On the 9th day of consuming the standarized diet plus chicken-based broth | Timing of clock gene expression change based on every 2-hour blood draws during the 24 hour admission on the 9th day of consuming the standardized diet plus chicken-based broth |
| Concentrations of Plasma Cytokine (TNA-alpha, IL-1, IL-6, IL-12, IL-17, IL-18, IL-23, IL-10, TGB-beta) | On the 9th day of consuming the standarized diet plus chicken-based broth | Changes in plasma cytokines based on every 2-hour blood draws during the 24 hour admission on the 9th day of consuming the standardized diet plus chicken-based broth |
| Flow Cytometric Analysis of Circulating Immune Cells (CD3+, CD4+, CD8+, CD14+, CD45+) | On the 9th day of consuming the standarized diet plus chicken-based broth | Change in circulating immune cell proportions based on every 2-hour blood draws during the 24 hour admission on the 9th day of consuming the standardized diet plus chicken-based broth |
Countries
United States
Participant flow
Recruitment details
A total of 68 participants were screened for eligibilty in the study between November 2020 to April 2025.
Pre-assignment details
A total of 7 participants who were screened decided not to participate before randomization because of inability to adhere to time requirements of the study or the study diets. This left 61 participants who were enrolled in the study.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 36 Years STANDARD_DEVIATION 6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 23 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 0 / 53 |
| other Total, other adverse events | 0 / 53 | 0 / 53 |
| serious Total, serious adverse events | 0 / 53 | 0 / 53 |
Outcome results
None listed