Deletion of Melanin Concentrating Hormone Receptor-1 disrupts overeating in the presence of food cues
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.
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2018, International Journal of Developmental NeuroscienceCitation Excerpt :Following a period of access to food to ensure testing under non-deprived conditions, presentation of the CS+ cue evokes an increase in sucrose intake significantly beyond that seen following CS− presentation or periods when no stimuli are presented (Johnson, 2013; Sherwood et al., 2015; Dailey et al., 2016). Using licking microstructure analyses, we have revealed that the basis for this overeating in part reflects conditioned increases in the palatability of food as revealed by an increase in burst size (using the 1000 ms pause criterion) that is specific to CS+ evoked consumption of the sucrose US (Sherwood et al., 2015; Sherwood et al., 2015; Johnson, 2017). In addition to classical conditioning, instrumental actions can also influence outcome palatability (Lydall et al., 2010; Johnson and Gallagher, 2011).
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2017, Pharmacology and TherapeuticsCitation Excerpt :Subsets of orexin neurons in lateral hypothalamus secrete the orexigenic neuropeptide MCH and have input to accumbens (Georgescu et al., 2005; Sears et al., 2010). The role of MCH-1 receptors in cue-potentiated feeding of palatable food is supported by findings that sated MCH-1 receptor knockout mice fail to overconsume sucrose in response to a conditioned stimulus, relative to sated wild-type mice (Sherwood et al., 2015). Thus, cue-potentiated feeding requires intact MCH-1 receptor signaling.