Mice without the Regulator Gene Rsc1A1 Exhibit Increased Na⁺-d-Glucose Cotransport in Small Intestine and Develop Obesity

Abstract

The product of the intronless single copy gene RSC1A1, named RS1, is an intracellular 617-amino-acid protein that is involved in the regulation of the Na ؉ -D-glucose cotransporter SGLT1. We generated and characterized RS1 knockout (RS1 ؊/؊ ) mice. In the small intestines of RS1 ؊/؊ mice, the SGLT1 protein was up-regulated sevenfold compared to that of wild-type mice but was not changed in the kidneys. The upregulation of SGLT1 was posttranscriptional. Small intestinal D-glucose uptake measured in jointly perfused small bowel and liver was increased twofold compared to that of the wild-type, with increased peak concentrations of D-glucose in the portal vein. At birth, the weights of RS1 ؊/؊ and wild-type mice were similar. At the age of 3 months, male RS1 ؊/؊ mice had 5% higher weights and 15% higher food intakes, whereas their energy expenditures and serum leptin concentrations were similar to those of wild-type mice. At the age of 5 months, male and female RS1 ؊/؊ mice were obese, with 30% increased body weight, 80% increased total fat, and 30% increased serum cholesterol. At this age, serum leptin was increased, whereas food intake was the same as for wild-type mice. The data suggest that the removal of RS1 leads to leptin-independent up-regulation of food intake, which causes obesity.Glucose absorption in the small intestine is essential for energy supply through carbohydrates. It is mediated by two transporters in the enterocytes, the sodium-dependent D-glucose cotransporter SGLT1 in the brush border membrane and the sodium-independent glucose transporter GLUT2 in the basolateral membrane (11). Na ϩ -D-glucose cotransporter expression and activity in the small intestine exhibits circadian periodicity and is increased following a carbohydrate-rich diet (5, 27). The regulation of SGLT1 can be mediated by adrenergic innervation, insulin, glucagon 37, glucagon-like peptide 2, and cholecystokinin (2,13,14,29,30). SGLT1 may be regulated by changes in transcription (23, 35), mRNA stability (21), endocytosis (12), and transport activity within the plasma membrane (34).Previously, several related 67-kDa polypeptides from humans, pigs, and rabbits, termed RS1, which show about 70% amino acid identity and are involved in the regulation of SGLT1, were cloned (17,18,26,36). The RS1 polypeptides are encoded by intronless single copy genes (RSC1A1 on chromosome 1p36.1 in humans). These genes are expressed in many cell types, including small intestinal enterocytes and renal proximal tubular cells (18,26,36). RS1 contains consensus sequences for protein kinase C and casein kinase II and a ubiquitin-associated domain that is conserved between different species (33). The RS1 protein is localized intracellularly and associated with the plasma membrane (33).Coexpression experiments with Xenopus laevis oocytes showed that human RS1 (hRS1) is involved in posttranscriptional down-regulation of hSGLT1 (18,26,36,37). The downregulation of hSGLT1 by hRS1 was dynamin dependent and increased by activation of protein kinase C (PKC) (37)...

Capsaicin-sensitive vagal afferents modulate posttranscriptional regulation of the rat Na+/glucose cotransporter SGLT1

“…Of note, in the RS1-null mouse model, SGLT1 protein expression is increased but mRNA is unchanged (27), a further example of induced discordance between SGLT1 mRNA and protein.…”

“…Dysregulation of SGLT1 is increasingly recognized in type 2 diabetes mellitus, with expression increasing up to fourfold in both patients and animal models (4, 7-9). Similarly, knockout of the SGLT1 regulatory subunit protein RS1 in mice leads to both SGLT1 overexpression and severe obesity (27). Therapy aimed at modulating SGLT1 expression may therefore have clinical benefits in diabetes and obesity through slowing of glucose absorption in a manner similar to amylase inhibitors (5) and through increased ileal glucose delivery (38).…”

Tripeptides of RS1 (RSC1A1) Inhibit a Monosaccharide-dependent Exocytotic Pathway of Na+-d-Glucose Cotransporter SGLT1 with High Affinity

“…Previously, we identified the intracellular protein RS1 (human gene RSC1A1) that participates in the transcriptional and post-transcriptional regulation of SGLT1 (21,(23)(24)(25)(26)(27)(28). RSC1A1 is an intronless single copy gene that was only detected in mammals and codes for 67-68-kDa proteins in human, pig, rabbit, and mouse that exhibit about 70% amino acid identity.…”

Physiologic changes in obesity and patient preparation for bariatric surgery

“…[36,37] When activated, the capacity of these receptors increase the availability of intestinal sodium-dependent glucose cotransporter-1 (SGLT-1) and glucose transporter-2 (GLUT2). [37,38] These are all important transporters for glucose absorption. [39] Activation of STRs and/or glucose transporters (GTs) has also been reported to trigger the release of incretin hormones.…”

“…[36][37][38][39][40][41] Animal experiments have shown that intestinal glucose absorption is dependent on the presence of luminal glucose or sweet nutrients via activation of intestinal sweet taste receptors (STRs), which are heterodimers of G-protein-coupled receptors. [36,37] When activated, the capacity of these receptors increase the availability of intestinal sodium-dependent glucose cotransporter-1 (SGLT-1) and glucose transporter-2 (GLUT2). [37,38] These are all important transporters for glucose absorption.…”