Gut-Specific Neprilysin Deletion Increases Insulin Secretion in High-Fat–Fed Mice

Global deletion of the ubiquitous peptidase neprilysin (NEP) protects against high fat diet (HFD)-induced insulin secretory dysfunction. Since NEP is expressed in the gut, it can cleave locally produced insulinotropic peptides. We previously found that under physiological conditions, acute inhibition of gut NEP enhances glucose-stimulated insulin secretion (GSIS) in mice. Thus, we determined whether this beneficial effect on GSIS also occurs in mice with gut-specific NEP deletion that are fed HFD. Mice with conditional deletion of NEP in enterocytes (NEPGut-/-) were generated by crossing Vil1-cre and floxed NEP mice. NEP activity was almost abolished throughout the gut in NEPGut-/- vs control mice (5±2 vs 164±20 vs 120±20 pmol MNA/h/μg, NEP Gut-/- vs Vil1-cre vs NEPfl/fl mice; n=5-6/group; p<0.0001), and was similar in plasma, pancreas and kidney among all mice. At 11 weeks of age, mice were fed HFD for 14 weeks, after which an OGTT was performed and GSIS assessed as ∆insulin/∆glucose from 0 to 10 min. Despite similar body weights in NEP Gut-/- and control mice, fasting plasma glucose was lower and GSIS higher in NEP Gut-/- vs controls (Table). In sum, gut-specific NEP deletion decreases fasting plasma glucose and increases GSIS in HFD-fed mice, suggesting gut NEP impairs ß-cell function under conditions of HFD. Thus, strategies to inhibit NEP specifically in the gut may protect against fat-induced ß-cell dysfunction.