Downregulation of intestinal sodium/glucose cotransporter‐1 is mediated by the short form of the leptin receptor (Ob‐Ra) (893.32)

We have shown that intestinal SGLT1 is decreased in leptin receptor (long form; Ob‐Rb) deficient mice. To determine if SGLT1 is regulated by leptin itself, we utilized Ob‐Rb deficient mice with compensatory increased leptin levels (db/db; n=6), leptin deficient mice (ob/ob; n=5), and their controls (db/con and ob/con, n=10 and 6, respectively). Db/db and ob/ob mice were obese (46±1 vs 27±2 g and 46±1 vs 25±1 g, respectively; P<0.01) and hyperglycemic (532±24 vs 120±4 mg/dl and 315±34 vs 168±9 mg/dl, respectively; P<0.01) vs controls. While Western blot and immunofluorescence revealed decreased apical membrane expression of SGLT1 in db/db mice vs db/con (44%±10 vs 100%±8; P<0.01), ob/ob mice had no change in membrane abundance. In contrast to the long form, the short form of leptin receptor (Ob‐Ra) is fully functional in db/db mice. To determine if leptin‐mediated downregulation of SGLT1 is mediated by Ob‐Ra, db/db (n=4) and db/con (n=5) were treated with the Ob‐Ra antagonist catestatin, a 20 amino acid fragment of chromogranin A (5 µg/g bw/day). After 6 days, blood glucose levels rose higher in db/db vs db/con mice (Δ change: 232±51 vs 50±12 mg/dl; P<0.05), which corresponded to a marked increase in SGLT1 membrane abundance via immunofluorescence in both groups. In conclusion, leptin signaling mediated by Ob‐Ra suppresses intestinal SGLT1 abundance, which may prevent exacerbated hyperglycemia in db/db mice. Grant Funding Source : Supported by P30DK079337, 5I01BX000323 and 10SDG2610034