Year of Publication

2018

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Pharmacology and Nutritional Sciences

First Advisor

Dr. Zhenheng Guo

Abstract

Arterial blood pressure (BP) undergoes a 24-hour oscillation that peaks in the active day and reaches a nadir at night during sleep in humans. Reduced nocturnal BP fall (also known as non-dipper) is the most common disruption of BP circadian rhythm and is associated with increased risk of untoward cardiovascular events and target organ injury. Up to 75% of diabetic patients are non-dippers. However, the mechanisms underlying diabetes associated non-dipping BP are largely unknown. To address this important question, we generated a novel diabetic db/db-mPer2Luc mouse model (db/db-mPer2Luc) that allows quantitatively measuring of mPER2 protein oscillation by real-time mPer2Luc bioluminescence monitoring in vitro and in vivo. Using this model, we demonstrated that the db/db-mPer2Luc mice have a diminished BP daily rhythm. The phase of the mPER2 daily oscillation is advanced to different extents in explanted peripheral tissues from the db/db-mPer2Luc mice relative to that in the control mice. However, no phase shift is found in the central oscillator, the suprachiasmatic nucleus (SCN). The results indicate that the desynchrony of mPER2 daily oscillation in the peripheral tissues contributes to the loss of BP daily oscillation in diabetes.

Extensive research over the past decades has been focused on how the components of food (what we eat) and the amount of food (how much we eat) affect metabolic diseases. Only recently has it become appreciated that the timing of food intake (when we eat), independent of total caloric and macronutrient quality, is also critical for metabolic health. To investigate the potential effect of the timing of food intake on the BP circadian rhythm, we simultaneously monitored the BP and food intake profiles in the diabetic db/db and control mice using radiotelemetry and BioDAQ systems. We found the loss of BP daily rhythm is associated with disrupted food intake rhythm in the db/db mice. In addition, the normal BP daily rhythm is altered in the healthy mice with abnormal feeding pattern, in which the food is available only during the inactive-phase. To explore whether imposing a normal food intake pattern is able to prevent and restore the disruption of BP circadian rhythm, we conducted active-time restricted feeding (ATRF) in the db/db mice. Strikingly, ATRF completely prevents and restorers the disrupted BP daily rhythm in the db/db mice. While multiple mechanisms likely contribute to the protection of ATRF on the BP daily rhythm, we found that ATRF improves the rhythms of energy metabolism, sleep-wake cycle, BP-regulatory hormones and autonomic nervous system (ANS) in the db/db mice. To further investigate the molecular mechanism by which ATRF regulates BP circadian rhythm, we determined the effect of ATRF on the mRNA expressions of core clock genes and clock target genes in the db/db mice. Of particular interest is that we found among all the genes we examined, the mRNA oscillation of Bmal1, a key core clock gene, is disrupted by diabetes and selectively restored by the ATRF in multiple peripheral tissues in the db/db mice. More importantly, we demonstrated that Bmal1 is partially required for ATRF to protect the BP circadian rhythm.

In summary, our findings indicate that the desynchrony of peripheral clocks contributes to the abnormal BP circadian pattern in diabetes. Moreover, our studies suggest ATRF as a novel and effective chronotherapy against the disruption of BP circadian rhythm in diabetes.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2018.464

Funding Information

This work is supported by the National Institutes of Health grants HL106843 and HL125228 and National Institute of General Medical Sciences grant P20 GM103527-05.

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