Early Overnutrition Results in Early-Onset Arcuate Leptin Resistance and Increased Sensitivity to High-Fat Diet

摘要

Roux-en-Y gastric bypass (RYGB) surgery is the most effective treatment for morbid obesity and remission of associated type 2 diabetes, but the mechanisms involved arepoorly understood. The aim of the present study was to develop and validate a rat model for RYGB surgery that allows repeated measurement of meal-induced changesingutandpancreatichormonesviachronicvenouscatheters.MaleSpragueDawleyratsmadeobeseonapalatablehigh-fatdietweresubjectedtoRYGBorshamsurgeryand compared with chow-fed, lean controls. Hormonal responses to a mixed-liquid test meal were examined by frequent blood sampling through chronically implantedjugular catheters in freely behaving rats, 3-4 months after surgery, when RYGB rats had significantly reduced body weight and fat mass compared with sham-operatedrats.Hyperleptinemia,basalhyperinsulinemia,andhyperglycemiaaswellaspostprandialglucoseintoleranceseeninsham-operated,obeseratswerecompletelyreversedby RYGB and no longer different from lean controls. Postprandial increases in glucagon-like peptide-1, peptide YY, and amylin as well as suppression of ghrelin levelswereallsignificantlyaugmentedinRYGBratscomparedwithbothsham-operatedobeseandleancontrolrats.Thus,ourratmodelreplicatesmostofthesalienthormonalandglycemicchangesreportedinobesepatientsafterRYGB,withtheadditionofamylintothelistofpotentialcandidatehormonesinvolvedinhypophagia,weightloss,and remission of diabetes. The model will be useful for elucidating the specific peripheral and central mechanisms involved in the suppression of appetite, loss of bodyweight, and remission of type 3 diabetes.