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: Jessica A Dominguez Rieg, Venkat R Chirasani, Hermann Koepsell, Sanjib Senapati, Sushil K Mahata, Timo Rieg
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 96 Issue 1 Pg. 98-111 (Jan 2016) ISSN: 1530-0307 [Electronic] United States
• PMID: 26552046 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Blood Glucose
• Chromogranin A
• Leptin
• Peptide Fragments
• Slc5a1 protein, mouse
• Sodium-Glucose Transporter 1
• chromogranin A (344-364)

Topics

• Amino Acid Sequence
• Animals
• Apoptosis
• Blood Glucose
• Body Weight
• Cell Proliferation
• Chromogranin A (chemistry, metabolism)
• Diabetes Mellitus, Experimental (metabolism)
• Gene Knockout Techniques
• Jejunum (metabolism)
• Leptin (chemistry, metabolism)
• Male
• Mice
• Mice, Transgenic
• Models, Molecular
• Molecular Sequence Data
• Peptide Fragments (chemistry, metabolism)
• Sodium-Glucose Transporter 1 (genetics, metabolism)