Intestinal Sodium Glucose Transporter 3 (SGLT3) is Downregulated in Experimental Models of Obesity and in Morbidly Obese Patients
Authors: Sotak Matus , Casselbrant Anna , Strömstedt Maria , Rath Eva , Adingupu Damilola , Karlsson Daniel , Fredin Maria Fritsch , Ergang Peter , Zietek Tamara , Pácha Jiří , Börgeson Emma , Hansen Pernille B. L. , Ericsson Anette , Granqvist Anna Björnson , Wallenius Ville , Fändriks Lars , Unwin Robert J. 
Published: June 2021

Study Objective

Impaired regulation of intestinal glucose transporters, including sodium glucose transporter 1 (SGLT1), has been suggested to play a role in obesity‐related cardio‐metabolic pathophysiology. Although evidence indicates that SGLT3 may be involved in intestinal glucose sensing, its role in obesity is not known. Here we report that intestinal SGLT3 expression is downregulated both in experimental models of obesity and in obese patients compared with lean controls.

Methods

Expression of the two Sglt3 isoforms Slc5a4a (coding Sglt3a) and Slc5a4b (coding Sglt3b) was determined in murine intestinal tissue and murine intestinal organoids using qPCR and RNAscope in‐situ hybridization. Expression of the transporters was studied in lean C57BL/6 male mice and in leptin‐deficient experimental models of obesity: C57BL/6J ob/ob−/− and Black and Tan BRachyury (BTBR) ob/ob−/− mice, with their respective lean littermates ob/ob+/? controls. To correlate experimental findings with human pathophysiology, jejunal biopsies were obtained endoscopically from lean volunteer controls and obese patients undergoing Roux‐en‐Y gastric bypass (RYGB) surgery. Furthermore, an additional biopsy was obtained from RYGB patients 6 months post‐surgery, at which time they had lost on average 29.4 % of their body weight. SGLT3 protein expression in human intestine was analyzed by western blot and immunohistochemistry.

Results

In‐situ hybridization and qPCR revealed that Sglt3a and Sglt3b were localized in the small intestine segments (duodenum, jejunum, ileum), but not in the large intestine, in lean C57BL/6 mice. The expression of both isoforms was detected primarily in epithelial cells and this observation was confirmed in murine intestinal organoids. Furthermore, Sglt3a and Sglt3b expression was reduced in murine models of obesity. Specifically, the expression of Sglt3a and Sglt3b mRNA was significantly downregulated in duodenum and jejunum of the leptin‐deficient obesity models C57BL/6J ob/ob−/− and BTBR ob/ob−/− mice, as compared with lean littermates. In human obese patients, jejunal SGLT3 protein expression was significantly lower than in healthy lean individuals. Moreover, 6 months after RYGB weight‐loss surgery, the patients exhibited restored SGLT3 protein expression in jejunal biopsies.

Conclusion

We report for the first time that SGLT3 expression is altered in experimental models of obesity and in morbidly obese patients. It is noteworthy that intestinal SGLT3 expression in obese patients was restored following weight‐loss RYGB surgery. The SGLT3 expression was mainly located in the intestinal epithelium, although further analysis is needed to decipher the specific role of SGLT3 in obesity.

Support or Funding Information

The project was funded by AstraZeneca.

The Börgeson lab is supported by the Knut & Alice Wallenberg Foundation, Wallenberg Centre for Molecular & Translational Medicine, the Swedish Research Council, (no. 2016/82), the Swedish Society for Medical Research (no. S150086), Åke Wiberg's Foundation (no. M15‐0058), Konrad & Helfrid Johansson's foundation.

MS received support from Wilhelm och Martina Lundgrens foundation (no. 2017‐1850) and Sigurd and Elsa Goljes foundation (no. LA2017‐0454).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.