Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling

Abstract

Please cite this article in press as: Valdivia, S., et al., Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling. Psychoneuroendocrinology (2015) and time-limited exposed to a high-fat diet (HFD) display robust binge eating events that gradually escalate over the initial accesses. Intake escalation is proposed to be part of the transition from a controlled to a compulsive or loss of control behavior. Here, we used a combination of behavioral and neuroanatomical studies in mice daily and time-limited exposed to HFD to determine the neuronal brain targets that are activated -as indicated by the marker of cellular activation c-Fos -under these circumstances. Also, we used pharmacologically or genetically manipulated mice to study the role of orexin or ghrelin signaling, respectively, in the modulation of this behavior. We found that four daily and time-limited accesses to HFD induce: (i) a robust hyperphagia with an escalating profile, (ii) an activation of different sub-populations of the ventral tegmental area dopamine neurons and accumbens neurons that is, in general, more pronounced than the activation observed after a single HFD consumption event, and (iii) an activation of the hypothalamic orexin neurons, although orexin signaling blockage fails to affect escalation of HFD intake. In addition, we found that ghrelin receptor-deficient mice fail to both escalate the HFD consumption over the successive days of exposure and fully induce activation of the mesolimbic pathway in response to HFD consumption. Current data suggest that the escalation in high fat intake during repeated accesses differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling.

Growth hormone secretagogue receptor signalling affects high‐fat intake independently of plasma levels of ghrelin andLEAP2, in a 4‐day binge eating model

“…The i.c.v.‐injected ghrelin tended to increase HF intake on experimental day 1, and such an increment masked HF intake escalation over the successive days. Furthermore, i.c.v.‐injected LEAP2 1‐14 reduced binge‐like HF intake in a similar fashion to that seen previously in GHSR‐deficient mice . These observations indicate that GHSR activity in the brain affects binge‐like HF intake in mice.…”

“…By contrast to WT mice, GHSR‐deficient mice do not display conditioned place preference for HF diet upon caloric restriction or chronic stress, whereas mice with expression of GHSR selectively in catecholaminergic cells, including the dopamine VTA neurones, show a conditioned place preference for HF diet after chronic stress similar to that seen in WT mice . Previous studies showing that GHSR‐deficient mice exhibit a smaller binge‐like HF intake also reported that these mice display a concomitant reduced activation of the mesolimbic pathway . Thus, it appears reasonable to hypothesise that centrally‐injected GHSR inverse agonists reduce binge‐like HF intake as a result of its action on the mesolimbic pathway.…”

“…Studies in which rodents have daily or intermittent access to a palatable diet for either short or long term have made evident a link between GHSR activity and different features of binge eating. In the present study, we investigated the role of GHSR activity on the early stage of our binge‐like eating protocol, when total daily food intake and body weight are unaffected . At this early stage, 2‐hour HF intake increases across the binge‐like eating events and then stabilises .…”

“…Studies in rodents provided additional evidence linking GHSR activity and binge eating . In particular, satiated GHSR‐deficient mice daily and time‐limited exposed to high‐fat (HF) diet display an attenuated binge‐like HF intake compared to WT mice . Interestingly, the lack of GHSR reduces binge‐like intake over the initial accesses to palatable food, when daily HF intake gradually escalates and is recognised as the transition period from a controlled to an uncontrolled behaviour .…”

Dietary triglycerides as signaling molecules that influence reward and motivation

“…Animals exposed to a restricted amount of calories from high-fat but not high-sugar diet exhibit decreased attention and increased impulsivity as assessed by 5-choice serial reaction task (5CSRT) **[34] . Limited exposure to a fat source also triggers binge-like eating behavior and increased sensitivity of ML activity, interestingly mice lacking ghrelin-receptor failed to escalate palatable food intake suggesting that energy-related signal such as ghrelin play also a role in ML response to energy-dense food **[35] . y.…”