Timing of Sodium Intake and Nocturnal Sodium Excretion and Blood Pressure in Obese African Americans

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.

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

Early sodium load: participants will consume a standardized diet providing 2.3 g of sodium per day for 7 days (run-in period), after which they will continue to consume the standardized diet for 9 days and in addition will take 2 g of sodium in the form of salt tablets with breakfast each day.

Late sodium load: participants will consume a standardized diet providing 2.3 g of sodium per day for 7 days (run-in period), after which they will continue to consume the standardized diet for the next 9 days and in addition will take 2 g of sodium with dinner each day.

Participants will receive dietary sodium supplementation in the form of tablets to be taken either with breakfast or dinner.

Difference in the rise of plasma melatonin during the night under dim-light conditions between study arms

Difference in buccal cell clock gene expression (CLOCK, Bmal1, per1, per2, Rev-erb-alpha, cry1, cry2) between study arms. Measures of clock gene expression will all be analyzed as fold change from baseline.

Peripheral blood monocyte clock gene (CLOCK, Bmal1, per1, per2, Rev-erb-alpha, cry1, cry2) expression

Difference in peripheral blood monocyte clock gene ((CLOCK, Bmal1, per1, per2, Rev-erb-alpha, cry1, cry2)) expression between study arms. Measures of clock gene expression will all be analyzed as fold change from baseline.

Difference in flow cytometric analysis of circulating immune cells (CD3+, CD4+, CD8+, CD14+, CD45+) between study arms. All flow cytometric analyses will be analyzed as percentage of total nucleated cells.

Concentrations of plasma cytokine (TNA-alpha, IL-1, IL-6, IL-12, IL-17, IL-18, IL-23, IL-10, TGB-beta)

Difference in plasma cytokine measures ((TNA-alpha, IL-1, IL-6, IL-12, IL-17, IL-18, IL-23, IL-10, TGB-beta) between study arms. All cytokine measurements will be analyzed as pg/ml.

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