Diet-induced obesity causes ghrelin resistance in reward processing tasks

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 (1mg/kg in 10ml/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 (20mg/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 (0.33μg/μl in 0.5μl) 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.

Obesity Impairs the Action of the Neuroendocrine Ghrelin System

“…VTA dopamine neurons regulate reward behaviors, and the role of ghrelin in such behaviors has attracted significant attention (reviewed in [41,61,62]. Intriguingly, ghrelin injection directly into the VTA still elicits food intake in DIO mice, similar to lean mice, suggesting that a HFD per se does not cause ghrelin resistance directly in the VTA [63]. To determine if DIO affects the ability of ghrelin to influence behavioral tasks associated with an internally rewarding state, conditioned place preference analysis was performed.…”

“…To determine if DIO affects the ability of ghrelin to influence behavioral tasks associated with an internally rewarding state, conditioned place preference analysis was performed. Indeed, intraperitoneal ghrelin paired with food availability in the conditioning chamber conditioned a place preference in chow-fed but not DIO mice [63]. Interestingly, intraperitoneal ghrelin in the absence of food during conditioning produced a place aversion in chow-fed and DIO mice, suggesting that separate neural circuits regulate conditioned place preference or aversion [63].…”

“…Second, the central responsiveness to the peripheral actions of ghrelin is reduced through the combined effect of reducing GHSR expression on target neurons, and through altered metabolic endocrine feedback in the DIO state. Third, ghrelin resistance occurs in different neural circuits regulating energy homeostasis, for example, ghrelin resistance in NPY/AgRP and/or nodose ganglion suppresses the hyperphagic effect of ghrelin [35,58], and ghrelin resistance occurs in neural pathways regulating reward processing and motivated behavior [63,64]. Furthermore, ghrelin itself during development programs the adult brain to respond appropriately to metabolic feedback, and impaired ghrelin function in this postnatal period may predispose individuals to obesity in adulthood.…”

Altered reward anticipation: Potential explanation for weight gain in schizophrenia?

“…For example, a chronically high-fat, high-sugar diet can lead to a down-regulation of D2 receptors in animals, mimicking the neural response to the chronic use of drugs that increase dopamine signaling (Alsiö et al, 2010;Lockie et al, 2015;Val-Laillet et al, 2015). This biologically strong effect has not been systematically studied in humans and its relation to reward anticipation remains unclear but it suggests that longitudinal neuroimaging studies of reward anticipation during altered food intake might reveal comparable phenomena in humans.…”

Dietary triglycerides as signaling molecules that influence reward and motivation

“…Molecular underpinnings linking nutrient overconsumption and altered neural function involve hypothalamic FFA metabolism [15], nutrient-induced endoplasmic reticulum (ER) stress [16-19], inflammatory processes [20], or resistance to energy-related signals [18,21-23]. …”