Gastric inhibitory polypeptide immunoneutralization attenuates development of obesity in mice.
Previous reports have suggested that the abrogation of gastric inhibitory polypeptide (GIP) signaling could be exploited to prevent and treat obesity and obesity-related disorders in humans. This study was designed to determine whether immunoneutralization of GIP, using a newly developed specific monoclonal antibody (mAb), would prevent the development of obesity. Specific mAb directed against the carboxy terminus of mouse GIP was identified, and its effects on the insulin response to oral and to intraperitoneal (ip) glucose and on weight gain were evaluated. Administration of mAb (30 mg/kg body wt, BW) to mice attenuated the insulin response to oral glucose by 70% and completely eliminated the response to ip glucose coadministered with human GIP. Nine-week-old C57BL/6 mice injected with GIP mAbs (60 mg·kg BW(-1)·wk(-1)) for 17 wk gained 46.5% less weight than control mice fed an identical high-fat diet (P < 0.001). No significant differences in the quantity of food consumed were detected between the two treatment groups. Furthermore, magnetic resonance imaging demonstrated that subcutaneous, omental, and hepatic fat were 1.97-, 3.46-, and 2.15-fold, respectively, lower in mAb-treated animals than in controls. Moreover, serum insulin, leptin, total cholesterol (TC), low-density lipoprotein (LDL), and triglycerides were significantly reduced, whereas the high-density lipoprotein (HDL)/TC ratio was 1.25-fold higher in treated animals than in controls. These studies support the hypothesis that a reduction in GIP signaling using a GIP-neutralizing mAb might provide a useful method for the treatment and prevention of obesity and related disorders.
Division of Gastroenterology, MetroHealth Medical Center and Case Western Reserve University, Cleveland, Ohio.
Michael O
MO
Boylan
Division of Gastroenterology, MetroHealth Medical Center and Case Western Reserve University, Cleveland, Ohio.
Patricia A
PA
Glazebrook
Division of Gastroenterology, MetroHealth Medical Center and Case Western Reserve University, Cleveland, Ohio.
Milos
M
Tatalovic
Division of Gastroenterology, MetroHealth Medical Center and Case Western Reserve University, Cleveland, Ohio michael.wolfe2@case.edu.
M Michael
MM
Wolfe
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000276:immunology*; D005749:Gastric Inhibitory Polypeptide / Q000037:antagonists & inhibitors / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods; D009765:Obesity / Q000175:diagnosis / Q000276:immunology* / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D005749:Gastric Inhibitory Polypeptide
gastric inhibitory polypeptide; immunoneutralization; monoclonal antibody; obesity