Intestinal Clock System and Glucose Metabolism

Shinsuke Onuma, Saori Kinoshita, Shigeki Shimba, Keiichi Ozono, Toshimi Michigami, Masanobu Kawai
Endocrinology, Volume 163, Issue 9, September 2022, bqac119
https://doi.org/10.1210/endocr/bqac119

Abstract

The circadian clock network is an evolutionarily conserved system that regulates systemic metabolism, such as glucose homeostasis. Intestinal tissue is a pivotal organ for the regulation of glucose metabolism, mainly via glucose absorption into the circulation; however, the significance of the intestinal circadian clock network for glucose metabolism remains largely unclear. We herein utilized a mouse model in which Bmal1, a core clock gene, was deleted in an intestine-specific manner (Bmal1_Int^−∕− mice) and demonstrated a rhythmic expression of Sglt1 with its peak at zeitgeber time (ZT) 10.7 ± 2.8 in control mice, whereas this was lost in Bmal1_Int^−∕− mice. Mechanistically, chromatin immunoprecipitation analysis revealed rhythmic binding of CLOCK to the E-box elements in the Sglt1 gene in control mice; however, this was absent in Bmal1_Int^−∕− mice. Accordingly, SGLT1 protein levels were decreased during the dark phase in Bmal1_Int^−∕− mice and this was associated with impaired glucose absorption, leading to a decline in hepatic glycogen levels at ZT4, which was restored by ingestion of high-sucrose water. Additionally, when mice were starved from ZT0, greater expression of the lipolysis-related gene Pnpla2 was observed in adipose tissue of Bmal1_Int^−∕− mice, and this was not noted when glycogen storage was restored by high-sucrose water prior to fasting, suggesting that higher Pnpla2 expression in Bmal1_Int^−∕− mice was likely caused by lower glycogen storage. These results indicate that disruption of the intestinal circadian clock system impairs glucose absorption in the intestine and affects systemic glucose homeostasis.

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