Abstract
Purpose :
The circadian rhythms generated by the suprachiasmatic nucleus (SCN) are responsible for various physiological and behavioral functions. While SCN lesioning resulted in weight gain and insulin resistance, restoring Bmal by a constitutively expressed promoter rescued insulin resistance and obesity in Bmal knockout (KO) mice. The db/db mice, a well-known animal model of type 2 diabetes (T2D), are arrhythmic and display neurovascular deficits of diabetic retinopathy (DR). However, strategies to overexpress BMAL centrally correct neurovascular deficits and circadian dysrhythmia of T2D remain unknown.
Methods :
The db/db mice were injected with AAV8-Bmal1 or a control virus stereotaxically in the SCN; the db/m mice received similar treatments. The wheel-running activity was determined to assess the circadian rhythm, and the retinal health was evaluated using optokinetic response (OKR) and electroretinogram (ERG). Additionally, the body composition, glucose tolerance test (GTT), insulin tolerance test (ITT), and pyruvate tolerance tests (PTT) were performed to assess the effects of BMAL1 overexpression on overall metabolic health. The norepinephrine (NE) levels were determined using ELISA to study the sympathetic drive.
Results :
The BMAL1 overexpression improved the free-running period of db/db mice; however, there was no effect on wheel-running activity. The db/db mice exhibited impaired OKR response, which was rescued by BMAL1 overexpression, including improved ERG b-wave and a-wave amplitudes under scotopic conditions. The BMAL1 overexpression reduced body weight and fat mass of db/db mice; however, there was no effect on lean body mass. BMAL1 overexpression improved glucose and pyruvate tolerance in db/db mice; however, insulin sensitivity remained unchanged. Finally, the db/db mice showed heightened levels of NE, which were downregulated in db/db mice where BMAL1 was overexpressed.
Conclusions :
Our studies demonstrate that BMAL1 overexpression improves retinal health and circadian rhythm in db/db mice; this effect is potentially mediated by increased glucose tolerance and decreased sympathetic drive. In conclusion, our studies have implications for future strategies to correct the central clock for improving retinal health in T2D.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.