Elsevier

Physiology & Behavior

Volume 152, Part B, 1 December 2015, Pages 402-407
Physiology & Behavior

Deletion of Melanin Concentrating Hormone Receptor-1 disrupts overeating in the presence of food cues

https://doi.org/10.1016/j.physbeh.2015.05.037Get rights and content

Highlights

  • Overeating in the presence of food cues was examined.

  • MCH-1R knockout mice were tested for cue potentiated feeding.

  • Deletion of MCH-1R disrupted cue potentiated feeding.

  • This disruption reflected reduction in size and number of licking bursts.

Abstract

Exposure to environmental cues associated with food can evoke eating behavior in the absence of hunger. This capacity for reward cues to promote feeding behaviors under sated conditions can be examined in the laboratory using cue-potentiated feeding (CPF). The orexigenic neuropeptide Melanin Concentrating Hormone (MCH) is expressed throughout brain circuitry critical for CPF. We examined whether deletion of the MCH receptor, MCH-1R, would in KO mice disrupt overeating in the presence of a Pavlovian CS + associated with sucrose delivery. While both wild-type controls and KO mice showed comparable food magazine approach responses during the CPF test, MCH-1R deletion significantly impaired the ability of the CS + to evoke overeating of sucrose under satiety. Through the use of a refined analysis of meal intake, it was revealed that this disruption to overeating behavior in KO mice reflected a reduction in the capacity for the CS + to initiate and maintain bursts of licking behavior. These findings suggest that overeating during CPF requires intact MCH-1R signaling and may be due to an influence of the CS + on the palatability of food and on regulatory mechanisms of peripheral control. Thus, disruptions to MCH-1R signaling may be a useful pharmacological tool to inhibit this form of overeating behavior.

Introduction

The obesogenic environment is characterized by a sedentary lifestyle and the availability of energy dense foods that can be acquired at little cost [1]. However, the detrimental effects of this environment are proving costly for our society as it contributes to weight gain, obesity and associated co-morbidities (e.g., heart disease and diabetes) [2]. This affects not only obese individuals whose quality of life is severely reduced, but also society in general, where in the US alone associated annual healthcare costs are estimated to be in excess of $190 billion [3]. At the same time, there is a lack of available pharmacotherapeutic strategies to aid in reducing body weight in obese individuals [4]. Thus, there is a critical need to identify the variables that influence overeating of food and the underlying brain mechanisms controlling this behavior.

Food-associated cues (e.g., television advertisements, radio jingles, and catchy signboards) likely contribute to eating by altering food preferences and enhancing consumption [5], which may promote weight gain and obesity. In the laboratory it is possible to examine the influence of food cues on eating behaviors using cue-potentiated feeding (CPF), where external cues paired with food delivery lead to significant overeating behavior under non-deprived conditions [5], [6]. This learned overeating response has been revealed in mice [7], rats [6], [8], and humans [9], [10], with foods of varying degrees of nutrition and palatability. CPF has been shown to depend on limbic and prefrontal circuitry that includes the lateral hypothalamus (LH) [11], basolateral amygdala (BLA) [6], ventral hippocampus (VH) [12] and ventromedial prefrontal cortex (vmPFC) [13].

Due to its synthesis in the LH [14], [15] and projections through both CPF and classical reward circuits [16], the central feeding peptide Melanin Concentrating Hormone (MCH) may play a critical role in influencing eating in the presence of reward cues. MCH exerts its physiological effects by binding to and activating the G protein-coupled MCH receptors, MCH-1R and MCH-2R. While in several species (e.g., primates, dogs and ferrets) the action of MCH-2R is preserved [17], in rodents it is either absent or non-functional [18]. MCH is upregulated during periods of food withdrawal or in hypoleptinemic ob/ob mice [19], [20], and elicits food intake when infused centrally [21], [22]. Transgenic overexpression of MCH also leads to hyperphagia and weight gain [23], whereas deletion or antagonism of MCH-1R suppresses intake [24], [25]. With respect to reward learning, MCH influences both food-seeking and cocaine-seeking [26], [27], [28], and deletion of MCH-1R disrupts conditioning of incentive motivation to a reward-paired auditory cue, leading to reductions in its ability to promote novel instrumental nose-poke responding [29].

Given this expression in CPF circuitry and its role in the regulation of food intake and reward learning, we hypothesized that MCH would play a significant role in CPF. Here we used a lack-of-function approach through MCH-1R gene knockout (KO) mice [18]. Under food-deprived conditions, mice were trained to acquire a simple Pavlovian discrimination followed by ad-libitum access to lab chow for a period of ≥ 3 days. After this satiety treatment, we examined the ability of food cues to promote overeating under non-deprived conditions. Furthermore, we used microstructure analyses to examine the variables that may underlie any changes in consummatory behavior (e.g., orosensory positive feedback and/or conditioned negative feedback) [30], [31], [32].

Section snippets

Subjects

The inactivation of the MCH-1R allele and the generation of KO animals and the genotyping method have been previously described [33]. Heterozygous MCH-1R+/− mice were backcrossed a minimum of eight times to the C57BL/6J strain (Jackson Laboratory, Bar Harbor, ME, USA). Seventeen WT and thirteen KO mice were used and were tested at approximately 3 months old, and were housed three or four to a cage under a 12 h light/dark cycle (lights on at 07:00–19:00 h). Food deprivation began at least 2 days

Pavlovian training and prefeeding

During Pavlovian training both WT and KO mice showed similar acquisition of the simple discrimination (Fig. 1). Three-way ANOVA revealed a main effect of cue (F(1,27) = 52.94, p < 0.001), block (F(3,81) = 7.06, p < 0.001) and an interaction between the two variables (F(1,27) = 20.58, p < 0.001). No effect of group nor its interaction among the variables was revealed (F's < 1, p's > 0.89).

In addition to comparable acquisition of the Pavlovian discrimination, both groups of mice had similar weights throughout

Discussion

Deletion of MCH-1R significantly reduced the ability of a Pavlovian CS + to evoke overeating under non-deprived conditions. Despite this effect on CPF, KO mice showed equivalent lick rates during baseline, CS − and ITI periods. Moreover, during the CPF test the CS + elicited similar approach behavior to the food magazine in both WT and KO mice. Thus, MCH-1R KO mice entered the magazine during presentations of the CS +; however, whilst there, they failed to engage in prolonged cue-evoked consumption

Conclusions

The media advertisements and other stimuli that we are exposed to on a daily basis are often associated with food and may be triggering feeding in the absence of a need for calories [5]. CPF provides a reliable model to examine overeating behavior across species [6], [7], [8], [9], [10]. Furthermore, these effects are typically uncompensated for by internal regulatory mechanisms [54]. CPF may also be relevant for studies examining eating disorders, as the rapid consumption of large amounts of

Acknowledgments

These studies was supported by NIDDK grant R21-DK84415 to A.W.J.

References (59)

  • C.P. Tan et al.

    Melanin-concentrating hormone receptor subtypes 1 and 2: species-specific gene expression

    Genomics

    (2002)
  • F. Presse et al.

    Melanin-concentrating hormone is a potent anorectic peptide regulated by food-deprivation and glucopenia in the rat

    Neurosci.

    (1996)
  • E.A. Duncan et al.

    The regulation of alcohol intake by melanin-concentrating hormone in rats

    Pharmacol. Biochem. Be.

    (2006)
  • A.W. Johnson et al.

    An analysis of licking microstructure in three strains of mice

    Appetite

    (2010)
  • G.P. Smith

    John Davis and the meanings of licking

    Appetite

    (2001)
  • P. Holland et al.

    A neural systems analysis of the potentiation of feeding by conditioned stimuli

    Physiol. Behav.

    (2005)
  • G.D. Petrovich et al.

    Control of food consumption by learned cues: a forebrain–hypothalamic network

    Physiol. Behav.

    (2007)
  • C.A. Pérez et al.

    Molecular annotation of integrative feeding neural circuits

    Cell Metab.

    (2011)
  • K.C. Berridge

    Measuring hedonic impact in animals and infants: microstructure of affective taste reactivity patterns

    Neurosci. Biobehav. Rev.

    (2000)
  • H.J. Grill et al.

    The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats

    Brain Res.

    (1978)
  • S. Peciña et al.

    Opioid site in nucleus accumbens shell mediates eating and hedonic “liking” for food: map based on microinjection Fos plumes

    Brain Res.

    (2000)
  • M. Tadayyon et al.

    Expression of melanin-concentrating hormone receptors in insulin-producing cells: MCH stimulates insulin release in RINm5F and CRI-G1 cell-lines

    Biochem. Biophys. Res. Commun.

    (2000)
  • P. Sterling

    Allostasis: a model of predictive regulation

    Physiol. Behav.

    (2012)
  • C.J. Reppucci et al.

    Learned food-cue stimulates persistent feeding in sated rats

    Appetite

    (2012)
  • H.-R. Berthoud

    The neurobiology of food intake in an obesogenic environment

    Proc. Nutr. Soc.

    (2012)
  • P.C. Holland et al.

    Rats with basolateral amygdala lesions show normal increases in conditioned stimulus processing but reduced conditioned potentiation of eating

    Behav. Neurosci.

    (2001)
  • G.D. Petrovich

    Amygdalar and prefrontal pathways to the lateral hypothalamus are activated by a learned cue that stimulates eating

    J. Neurosci.

    (2005)
  • G.D. Petrovich et al.

    Medial prefrontal cortex is necessary for an appetitive contextual conditioned stimulus to promote eating in sated rats

    J. Neurosci.

    (2007)
  • J.C. Bittencourt et al.

    The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization

    J. Comp. Neurol.

    (1992)
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