视交叉上核过表达Bmal1改善糖尿病小鼠视网膜神经血管缺陷

原文

AIMS/HYPOTHESIS: The suprachiasmatic nucleus regulates circadian rhythms and influences physiological and behavioural functions. Clock genes not only play a critical role in orchestrating circadian rhythms, but also regulate a variety of bodily functions. While Bmal1, a clock gene, is vital for maintaining optimal circadian rhythms, its therapeutic potential in type 2 diabetes remains unexplored. METHODS: In this study, db/db mice, a well-established model of type 2 diabetes exhibiting arrhythmic behaviour and complications, were injected stereotaxically with AAV-Bmal1 or a control virus into the suprachiasmatic nucleus to evaluate the protective effects of Bmal1 overexpression on neurovascular deficits of type 2 diabetes. Given the complex neurovascular network and the eye's unique accessibility as a transparent system, ocular complications were selected as a model to examine the neuronal functional, behavioural and vascular benefits of central overexpression of Bmal1. RESULTS: Bmal1 overexpression decreased the free-running period, which otherwise is lengthened in db/db mice. Retinal neuronal function was restored on the electroretinogram, along with optomotor behaviour and visual acuity enhancements. Retinal vascular deficits were also significantly reduced. Notably, Bmal1 overexpression decreased fat content in genetically predisposed obese db/db mice compared with the untreated db/db group. As the suprachiasmatic nucleus is known to regulate hepatic glucose production via sympathetic mechanisms, glycaemic control and pyruvate tolerance tests were evaluated. Glucose homeostasis was improved in Bmal1-overexpressing mice, accompanied by a significant reduction in hepatic gluconeogenesis. Plasma noradrenaline (norepinephrine) and liver tyrosine hydroxylase levels were reduced, indicating a protective regulation of adrenergic signalling. CONCLUSIONS/INTERPRETATION: Our study highlights the therapeutic potential of central overexpression of a clock gene, Bmal1, to mitigate metabolic and neurovascular deficits of type 2 diabetes, offering a compelling framework for incorporating circadian rhythms into managing diabetes and its complications.