A Novel Diabetic Mouse Model for Real-Time Monitoring of Clock Gene Oscillation and Blood Pressure Circadian Rhythm

Oct 4, 2018Journal of biological rhythms

A new diabetic mouse model for real-time tracking of daily body clock genes and blood pressure rhythms

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Abstract

The diabetic db/db-mPer2 mouse model exhibits a compromised blood pressure daily rhythm.

Diabetic db/db-mPer2 mice are characterized by obesity, diabetes, and glucose intolerance.
Disruption of the blood pressure daily rhythm is linked to altered daily rhythms in baroreflex sensitivity and locomotor activity.
In db/db-mPer2 mice, the phase of the mPer2 daily oscillation is advanced in various peripheral tissues, including the liver and kidney.
No phase shift in mPer2 daily oscillation was observed in the suprachiasmatic nucleus (SCN) of db/db-mPer2 mice.
The findings indicate that desynchrony in mPer2 oscillations in peripheral tissues may contribute to the loss of blood pressure daily oscillation in diabetes.

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Diabetic patients have an increased prevalence of blood pressure (BP) circadian rhythm disruption, which is associated with an increased risk of target organ damage and detrimental cardiovascular events. Limited information is available regarding the role of clock genes in the disruption of BP circadian rhythm in diabetes due to the lack of a diabetic animal model that allows real-time monitoring of clock gene oscillation. Here, we generated a novel diabetic db/db-mPer2mouse model by crossing type 2 diabetic db/db mice with mPer2knock-in mice. The daily rhythms of BP, heart rate, locomotor activity, and food and water intake were acquired by radiotelemetry or using metabolic chambers. The daily oscillation of mPer2 bioluminescence was recorded by LumiCycle in real-time in tissue explants and using the IVIS system in vivo. Our results show that db/db-mPer2mice are obese, diabetic, and glucose intolerant. The db/db-mPer2mice displayed a compromised BP daily rhythm, which was associated with disrupted daily rhythms in baroreflex sensitivity, locomotor activity, and metabolism, but not heart rate or food and water intake. The phase of the mPer2 daily oscillation was advanced to different extents in the explanted peripheral tissues from db/db-mPer2mice relative to control mice. In contrast, no phase shift was detected in mPer2 daily oscillations in the explanted SCN. Moreover, advanced phase shift of the mPer2 daily oscillation was detected in the liver, kidney and submandibular gland in vivo of db/db-mPer2mice. In conclusion, the diabetic db/db-mPer2mouse is a novel animal model that allows real-time monitoring of mPer2 circadian rhythms ex vivo and in vivo. The results from db/db-mPer2mice suggest that the desynchrony of mPer2 daily oscillation in peripheral tissues contributes to the loss of BP daily oscillation in diabetes. Luc Luc Luc Luc Luc Luc Luc Luc

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A Novel Diabetic Mouse Model for Real-Time Monitoring of Clock Gene Oscillation and Blood Pressure Circadian Rhythm

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