Glycaemia and body weight are regulated by sodium-glucose cotransporter 1 (SGLT1) expression via O-GlcNAcylation in the intestine

• Published in: Molecular metabolism (Germany) Vol. 59; p. 101458
• Main Authors: Nishimura, Kimihiro, Fujita, Yukihiro, Ida, Shogo, Yanagimachi, Tsuyoshi, Ohashi, Natsuko, Nishi, Kiyoto, Nishida, Atsushi, Iwasaki, Yasumasa, Morino, Katsutaro, Ugi, Satoshi, Nishi, Eiichiro, Andoh, Akira, Maegawa, Hiroshi
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.05.2022; Elsevier
• Subjects: Animals; Blood Glucose - metabolism; Body Weight; GLP-1; Glucose - metabolism; Glucose absorption; Intestine; Intestines - metabolism; Mice; O-GlcNAcylation; Obesity; Original; SGLT1; Sodium-Glucose Transporter 1 - genetics; Tamoxifen; Glucose absorption; O-GlcNAcylation; GLP-1; Intestine; SGLT1
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2022.101458

The intestine is an important organ for nutrient metabolism via absorption and endocrine systems. Nutrients regulate O-GlcNAcylation, a post-translational modification of various proteins by O-GlcNAc transferase (OGT). We have previously shown that general OGT knockout induced severe weight loss and hypoglycaemia in mice, but little is known about how O-GlcNAcylation in the intestine modulates nutrient metabolism, especially glucose metabolism, through absorption. We aimed to reveal the roles of O-GlcNAcylation in glucose absorption by the small intestine and elucidate the mechanism by which O-GlcNAcylation regulates sodium-glucose cotransporter 1 (SGLT1) expression. First, we fasted normal mice and examined the changes in glucose transporters and O-GlcNAcylation in the intestine. Then, we generated two lines of small intestine-specific OGT-deficient mice (congenital: Ogt-VKO, tamoxifen-inducible: Ogt-iVKO) and observed the changes in body weight and in glucose and lipid metabolism. Finally, we investigated Sglt1 gene regulation by O-GlcNAcylation using enteroendocrine STC-1 cells. Fasting decreased O-GlcNAcylation in the intestinal epithelium of normal mice. The Ogt-VKO mice showed significantly lower non-fasted blood glucose levels and were underweight compared with litter matched controls. Glycaemic excursion in the Ogt-VKO mice was significantly lower during the oral glucose tolerance test but comparable during the intraperitoneal glucose tolerance test. Furthermore, the Ogt-VKO mice exhibited lower Sglt1 expression in the small intestine compared with the control mice. We obtained similar results using the Ogt-iVKO mice only after tamoxifen administration. The oral d-xylose administration test revealed that the intestinal sugar absorption was diminished in the Ogt-iVKO mice and that GLP-1 secretion did not sufficiently increase after glucose gavage in the Ogt-iVKO mice. When using STC-1 cells, O-GlcNAcylation increased Sglt1 mRNA via a PKA/CREB-dependent pathway. Collectively, loss of O-GlcNAcylation in the intestine reduced glucose absorption via suppression of SGLT1 expression; this may lead to new treatments for malabsorption, obesity and diabetes. [Display omitted] •Intestine-specific OGT depletion results in weight loss and hypoglycaemia.•It reduces SGLT1 expression, resulting in glucose absorption from the gut.•OGT knockdown may contribute to diminish glucose-induced incretin secretion.•OGT may regulate SGLT1 expression via the cAMP/CREB-dependent pathway.•O-GlcNAcylation regulates SGLT1 expression in the intestine and the kidney.