AUTHOR=Paulussen Frederik , Kulkarni Chetan P. , Stolz Frank , Lescrinier Eveline , De Graeve Stijn , Lambin Suzan , Marchand Arnaud , Chaltin Patrick , In't Veld Peter , Mebis Joseph , Tavernier Jan , Van Dijck Patrick , Luyten Walter , Thevelein Johan M. 

TITLE=The β2-adrenergic receptor in the apical membrane of intestinal enterocytes senses sugars to stimulate glucose uptake from the gut

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.1041930

DOI=10.3389/fcell.2022.1041930

ISSN=2296-634X

ABSTRACT=<p>The presence of sugar in the gut causes induction of SGLT1, the sodium/glucose cotransporter in intestinal epithelial cells (enterocytes), and this is accompanied by stimulation of sugar absorption. Sugar sensing was suggested to involve a G-protein coupled receptor and cAMP - protein kinase A signalling, but the sugar receptor has remained unknown. We show strong expression and co-localization with SGLT1 of the β2-adrenergic receptor (<italic>β</italic><sub>2</sub>-AR) at the enterocyte apical membrane and reveal its role in stimulating glucose uptake from the gut by the sodium/glucose-linked transporter, SGLT1. Upon heterologous expression in different reporter systems, the <italic>β</italic><sub>2</sub>-AR responds to multiple sugars in the mM range, consistent with estimated gut sugar levels after a meal. Most adrenergic receptor antagonists inhibit sugar signaling, while some differentially inhibit epinephrine and sugar responses. However, sugars did not inhibit binding of I<sup>125</sup>-cyanopindolol, a <italic>β</italic><sub>2</sub>-AR antagonist, to the ligand-binding site in cell-free membrane preparations. This suggests different but interdependent binding sites. Glucose uptake into everted sacs from rat intestine was stimulated by epinephrine and sugars in a <italic>β</italic><sub>2</sub>-AR-dependent manner. STD-NMR confirmed direct physical binding of glucose to the <italic>β</italic><sub>2</sub>-AR. Oral administration of glucose with a non-bioavailable <italic>β</italic><sub>2</sub>-AR antagonist lowered the subsequent increase in blood glucose levels, confirming a role for enterocyte apical <italic>β</italic><sub>2</sub>-ARs in stimulating gut glucose uptake, and suggesting enterocyte <italic>β</italic><sub>2</sub>-AR as novel drug target in diabetic and obese patients. Future work will have to reveal how glucose sensing by enterocytes and neuroendocrine cells is connected, and whether <italic>β</italic><sub>2</sub>-ARs mediate glucose sensing also in other tissues.</p>