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.