Diet-induced obesity causes ghrelin resistance in reward processing tasks. (December 2015)

• Record Type: Journal Article
• Authors: Lockie, Sarah H.; Dinan, Tara; Lawrence, Andrew J.; Spencer, Sarah J.; Andrews, Zane B.
• Is Part Of: Psychoneuroendocrinology. Volume 62(2015:Dec.)
• Page Start: 114
• Page End: 120
• Publication Date: 2015-12
• Subjects: Ghrelin -- Diet-induced obesity -- Ghrelin resistance -- Reward pathways -- Conditioned place preference -- Metabolic sensing; Psychoneuroendocrinology -- Periodicals; Endocrinology -- Periodicals; Neurology -- Periodicals; Psychiatry -- Periodicals; Neuropsychoendocrinologie -- Périodiques; 616.8
• DOI: 10.1016/j.psyneuen.2015.08.004
• Languages: English
• ISSNs: 0306-4530

Abstract

Highlights: Diet-induced obesity prevents a ghrelin-induced conditioned place preference to food. In the absence of food during conditioning, ghrelin causes a place aversion. The ghrelin conditioned aversion occurs independent of diet. Intra-VTA ghrelin injection increases food intake in chow and high fat fed mice. Ghrelin resistance to reward processing is not a direct action on VTA neurons. Abstract: Diet-induced obesity (DIO) causes ghrelin resistance in hypothalamic Agouti-related peptide (AgRP) neurons. However, ghrelin promotes feeding through actions at both the hypothalamus and mesolimbic dopamine reward pathways. Therefore, we hypothesized that DIO would also establish ghrelin resistance in the ventral tegmental area (VTA), a major site of dopaminergic cell bodies important in reward processing. We observed reduced sucrose and saccharin consumption in Ghrelin KO vs Ghrelin WT mice. Moreover, DIO reduced saccharin consumption relative to chow-fed controls. These data suggest that the deletion of ghrelin and high fat diet both cause anhedonia. To assess if these are causally related, we tested whether DIO caused ghrelin resistance in a classic model of drug reward, conditioned place preference (CPP). Chow or high fat diet (HFD) mice were conditioned with ghrelin (1 mg/kg in 10 ml/kg ip) in the presence or absence of food in the conditioning chamber. We observed a CPP to ghrelin in chow-fed mice but not in HFD-fed mice. HFD-fed mice still showed a CPP for cocaine (20 mg/kg), indicating that they maintained the ability to develop conditioned behaviour. The absence of food availability during ghrelin conditioning sessions induced a conditioned place aversion, an effect that was still present in both chow and HFD mice. Bilateral intra-VTA ghrelin injection (0.33 μg/μl in 0.5 μl) robustly increased feeding in both chow-fed and high fat diet (HFD)-fed mice; however, this was correlated with body weight only in the chow-fed mice. Our results suggest that DIO causes ghrelin resistance albeit not directly in the VTA. We suggest there is impaired ghrelin sensitivity in upstream pathways regulating reward pathways, highlighting a functional role for ghrelin linking appropriate metabolic sensing with reward processing.