GDF-15 is a secreted circulating polypeptide that regulates systemic energy balance. GDF-15 agonists may have therapeutic potential as anorectic agents in obesity and type 2 diabetes. The receptor for GDF-15, Gfral, is expressed on specific neurons in the area postrema (AP) of the hindbrain, and is necessary for the effect of GDF-15 on food intake. Given the role of the AP in vagal control of gastric motility, we sought to investigate the potential effects of GDF-15 on gastric emptying. Food intake reduction by GDF-15 was confirmed in C57Bl/6N mice using BioDAQ continuous food consumption monitoring. Animals were treated sc with recombinant His-tagged human GDF-15 prior to initiation of the dark cycle; GDF-15 treated mice showed significant reduction in food intake relative to vehicle treated controls (12 hour cumulative food intake: 3nmol/kg, -19.9±10.5%; 10nmol/kg, -58.0±10.0%; P<0.0001, n=8). Gastric emptying was assessed using an oral acetaminophen (AAP) absorption test over 90 minute using LC/MS detection. This method was validated using known inhibitor of gastric emptying, Exendin-4 as a positive control; 7.2nmol/kg Exendin-4 significantly reduced integrated AAP absorption by -44.7±5.1% (P<0.01, n=8). In this assay, GDF-15 caused a significant dose-dependent inhibition of gastric emptying, reducing acetaminophen AUC levels by -18.1±10.6% at 1nmol/kg, and by -36.0±9.9% at 10nmol/kg, relative to vehicle treated control mice (P<0.01, n=8). Comparable results were obtained in an independent repetition of the study. We extended the results obtained in mice to SD rats, where we similarly observed a significant reduction in gastric emptying following GDF-15 treatment. Hence, GDF-15 appears to reduce gastric emptying rate in both mouse and rat, potentially contributing to the food intake suppression mechanism of action.


S.A. Hinke: Employee; Self; Janssen Research & Development. C.R. Cavanaugh: Employee; Self; Janssen Research & Development. T. Kirchner: None. W. Lang: None. R. Meng: None. N.H. Wallace: None. J. Liu: None. K.E. D'Aquino: Employee; Self; Janssen Research & Development. Employee; Spouse/Partner; Janssen Research & Development. G. Ho: None. M.M. Rankin: Employee; Self; Janssen Research & Development. S. Wang: None. J.A. Chavez: None. S.M. Nelson: None. J. Furman: Employee; Self; Janssen Research & Development. S. Mullican: Employee; Self; Janssen Research & Development. S.M. Rangwala: Employee; Self; Janssen Research & Development. A.R. Nawrocki: Employee; Self; Janssen Pharmaceuticals, Inc..

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