GDF15 Induces an Aversive Visceral Malaise State that Drives Anorexia and Weight Loss

Abstract

Summary: The anorectic and weight-suppressive effects of growth differentiation factor-15 (GDF15) are attracting considerable attention for treating obesity. Current experiments in rats investigate whether GDF15 induces an aversive visceral malaise-based state that mediates its acute anorectic effect and, through aversion conditioning, exerts longer-term anorexia. Visceral malaise, conditioned affective food responses (taste reactivity), gastric emptying (GE), food intake, and body weight are evaluated after acute and chronic systemic dosing of GDF15 or long-acting Fc-GDF15. Pica, a marker of visceral malaise, is present at all anorectic GDF15 doses. Moreover, malaise induced by GDF15 does not decline over time, suggesting the lack of an improved tolerance after prolonged exposure. One association between GDF15 and novel food conditions a disgust/aversive response that persists beyond GDF15 acute action. Delayed GE is not a requirement for GDF15-induced anorexia. Clinical studies are required to evaluate whether GDF15’s aversive-state-based anorexia will be contraindicated as an obesity treatment. : Borner et al. show that the visceral malaise (i.e., pica) that accompanies GDF15-induced anorexia persists after prolonged exposure, denoting the lack of improved tolerance. Further, the food-GDF15 pairing conditions a disgust/aversive response that contributes to anorexia and lasts beyond GDF15’s acute action. Reduced gastric emptying is not required for GDF15-induced anorexia/malaise. Keywords: MIC-1, pica, taste reactivity, food aversion conditioning, affective response to food, gastric emptying, GFRAL, PBN, hindbrain