title: Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice.
abstract: The small intestine is the major site for nutrient absorption that is critical in maintenance of euglycemia. Leptin, a key hormone involved in energy homeostasis, directly affects nutrient transport across the intestinal epithelium. Catestatin (CST), a 21-amino acid peptide derived from proprotein chromogranin A, has been shown to modulate leptin signaling. Therefore, we reasoned that leptin and CST could modulate intestinal Na(+)-glucose transporter 1 (SGLT1) expression in the context of obesity and diabetes. We found that hyperleptinemic db/db mice exhibit increased mucosal mass, associated with an enhanced proliferative response and decreased apoptosis in intestinal crypts, a finding absent in leptin-deficient ob/ob mice. Intestinal SGLT1 abundance was significantly decreased in hyperleptinemic but not leptin-deficient mice, indicating leptin regulation of SGLT1 expression. Phlorizin, a SGLT1/2 inhibitor, was without effect in an oral glucose tolerance test in db/db mice. The alterations in architecture and SGLT1 abundance were not accompanied by changes in the localization of intestinal alkaline phosphatase, indicating intact differentiation. Treatment of db/db mice with CST restored intestinal SGLT1 abundance and intestinal turnover, suggesting a cross-talk between leptin and CST, without affecting plasma leptin levels. Consistent with this hypothesis, we identified structural homology between CST and the AB-loop of leptin and protein-protein docking revealed binding of CST and leptin with the Ig-like binding site-III of the leptin receptor. In summary, downregulation of SGLT1 in an obese type 2 diabetic mouse model with hyperleptinemia is presumably mediated via the short form of the leptin receptor and reduces overt hyperglycemia.
authors.affiliation: Department of Basic Sciences, Bastyr University California, San Diego, CA, USA.|VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Dominguez Rieg
authors.affiliation: Department of Biotechnology, Institute of Technology Madras, Chennai, India.
authors.forename: Venkat R
authors.initials: VR
authors.lastname: Chirasani
authors.affiliation: Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Würzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
authors.affiliation: Department of Biotechnology, Institute of Technology Madras, Chennai, India.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Senapati
authors.affiliation: VA San Diego Healthcare System, San Diego, CA, USA.|Division of Nephrology/Hypertension, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.affiliation: VA San Diego Healthcare System, San Diego, CA, USA.|Division of Nephrology/Hypertension, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Timo
authors.initials: T
authors.lastname: Rieg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose; D001835:Body Weight; D049109:Cell Proliferation; D053379:Chromogranin A / Q000737:chemistry / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D055786:Gene Knockout Techniques; D007583:Jejunum / Q000378:metabolism; D020738:Leptin / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D051269:Sodium-Glucose Transporter 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D053379:Chromogranin A; D020738:Leptin; D010446:Peptide Fragments; C495675:Slc5a1 protein, mouse; D051269:Sodium-Glucose Transporter 1; C109084:chromogranin A (344-364)