The intestine is critical in maintenance of euglycemia. We showed that intestinal SGLT1 is decreased in hyperleptinemic db/db mice, but not in leptin-deficient ob/ob mice. Only hyperleptinemic mice exhibit increased mucosal mass with longer villi and deeper crypts compared to controls. Catestatin (CST), a fragment of chromogranin A, can modulate leptin signaling. We conducted molecular dynamics simulations and found that CST mimics the AB-loop of leptin’s binding site-III. Pairwise sequence alignment between CST and the AB-loop showed >40% similarity. Both leptin and CST exhibit similar modes of binding to the leptin receptor by targeting the Ig-like domain. We hypothesized that CST treatment would affect leptin signaling in db/db mice resulting in better glycemic control and normalization of intestinal epithelial cell turnover. To understand the increased mucosal mass in hyperleptinemic mice, we quantified proliferation and apoptosis in the jejunum of db/db, ob/ob, and control (db/con, ob/con) mice (n=4-5/genotype). Compared to controls, db/db mice had more proliferating cell nuclear antigen-positive cells in the crypts (2,361±110 vs 1,453±211 cells; P<0.05) indicating an increased proliferative response, while cleaved caspase-3 staining, a marker for apoptosis, showed reduced apoptosis in the crypts (2.5±0.5 vs 9.5±0.5 cells; P<0.05) and villi tips (5±1 vs 9±1 cells; P<0.05). Proliferation and apoptosis were not different between control and ob/ob mice. Glucagon-like peptide (GLP)-2 is an intestinotrophic hormone that increases cell proliferation. We found that GLP-2 plasma levels are ~35% higher in db/db versus db/con mice (1.4±0.1 vs 1.0±0.1 pg/ml, P<0.001), and may contribute to the intestinal hyperplasia. In a separate cohort, we treated db/db (n=4) and db/con (n=5) mice for 7 days with CST (5 mg/kg/day i.p.). CST treatment not only restored intestinal SGLT1 expression but also normalized villus length and intestinal proliferation to levels found in controls. To study if there is a functional consequence of elevated leptin levels, we performed oral glucose tolerance tests (OGTT) by administering glucose (2 g/kg, 1% of bw via oral gavage) without or with phlorizin, an SGLT1/2 inhibitor (0.5 g/kg), to db/db and db/con mice (n=4-8/genotype). Blood glucose was measured at 0, 15, 30, 45, 60 and 120 min and the area under the curve (AUC) was calculated. Compared to vehicle, phlorizin significantly improved glycemic control in db/con mice (AUC: 13,857±4,051 vs 36,483±7,747; P<0.05) but was without effect in db/db mice (AUC: 12,794±4,675 vs 13,714±2,648; P=NS). Further, phlorizin treatment mimicked the OGTT profile of SGLT1 knockout mice (AUC: 6,325±2,535). In conclusion, CST may be a novel regulator that interferes with leptin signaling in hyperleptinemic mice and may lead to beneficial effects on intestinal turnover and restoration of SGLT1 abundance.