Comments by Emily E. Perszyk and Dana M. Small (March 2023).

The obesity epidemic is caused by an increase in the availability of inexpensive, palatable, and energy dense foods. However, not everyone is similarly susceptible. In 1968, Stanley Schachter proposed the externality theory of obesity, which posits that the relative strength of internal (e.g., gastric distension) versus external (e.g., food cues) factors on eating behavior predicts weight gain susceptibility: the stronger the bias towards external control, the higher the risk [1]. Thus, the main tenet of this theory, reviewed in Ingestive Classic #16, is that external cues override internal cues to promote intake beyond need.

In 1983, Harvey P. Weingarten provided the first direct experimental test of Schachter’s theory. The results, which he reported in Science, demonstrated that conditioned food cues cause sated rats to eat [2]. Today, this behavior is referred to as “cue-potentiated feeding,” and it has become an important tool for investigating the neural circuits underlying so-called “non-homeostatic” eating in rodents. It is also one of the key references supporting a role for “food cue reactivity” in driving human overeating, especially in the context of the obesogenic food environment [3,4].

Weingarten’s experiment consisted of separate conditioning and testing phases. The conditioning phase was conducted over 11 days. Six times per day, hungry rats were presented with a buzzer and a light (CS+) for four and a half minutes. In the final 30 seconds, a liquid meal of evaporated milk was provided. A photocell beam located at the front of the food cup enabled measurement of the latency with which the rats began to consume the meal. By conditioning day six, the time to initiate feeding had significantly decreased, an effect which endured for the remainder of the days in the conditioning phase. This indicated that the animals successfully learned that the presence of the CS+ predicted food availability. The sound of a pure tone (CS–) was also played during inter-meal intervals, such that it was never paired with food.

The testing phase was conducted over the subsequent 21 days. During this time, a bottle containing the liquid diet was continuously available, allowing the rats to feed freely. The key question was whether the presentation of the CS+ would influence food intake despite the constant availability of food and therefore in the absence of hunger. It did. On each testing day, the rats were presented with the CS+ and immediately began to eat. Moreover, the latency to begin eating was as fast as during the conditioning sessions, which took place when the animals were hungry. By contrast, the presence of the CS– did not elicit rapid feeding. These findings supported Schachter’s externality theory because they showed that conditioned food cues could override internal signals to trigger eating in a sated state. However, this effect could only be expected to support weight gain if animals failed to compensate for the increased intake by eating less later in the day.

To address this question, Weingarten performed a second experiment. Two types of test days were employed: signal days (with CS+ presentations) and nonsignal days (lacking CS+ presentations). If the animals were able to compensate, then the total amount consumed should be equivalent in signal and nonsignal days. This is exactly what happened; the rats reduced intake subsequent to the CS+ feeding bout so that the total amount consumed was almost identical across signal and nonsignal days. This suggested that cue-potentiated feeding might not support weight gain. However, Weingarten’s animals were lean and had not been exposed to a Western or high energy dense diet. He therefore could not rule out the possibility that animals or humans with obesity may fail to compensate and therefore gain weight.

Remarkably, this possibility remains untested today in either animals or humans; however, there is evidence that humans with obesity are more sensitive to cue-potentiated feeding, or what is more commonly referred to in humans as food cue reactivity. For instance, children with overweight consume more during a ‘cued’ buffet in which they are instructed to smell (but not taste) the foods prior to consumption versus in a ‘standard’ buffet where they can eat freely from the start [5]. By contrast, youth with healthy weight eat equivalent amounts to their overweight counterparts in the standard buffet, but do not increase consumption following cue exposure[5]. Likewise, individuals with high compared to low Body Mass Index (BMI) show elevated attentional biases [6], greater salivation [7], and stronger cravings [7,8] in response to food cues. These effects may be particularly strong in restrained versus unrestrained eaters [9] (see SSIB Ingestive Classics #17 for an explanation of the restrained eating model from Peter Herman and Deborah Mack). We have also shown that the tendency to eat more in the presence of food cues is associated with future increases in body fat percentage [10], supporting the possibility that this mechanism may be important for understanding overeating and weight gain susceptibility in humans.

While the effect of obesity on cue-potentiated feeding remains unknown in animals, the neural circuits underlying cue-potentiated feeding have been well mapped in the rodent model. In 2002, Petrovich and colleagues demonstrated that cue-potentiated feeding in the absence of hunger depends on intact connections between the basolateral amygdala and lateral hypothalamus [11]. This communication may rely on the orexigenic neuropeptide Melanin Concentrating Hormone (MCH) – which is synthesized in the lateral hypothalamus and highly expressed in the basolateral amygdala [12,13] – such that mice with genetic deletion of MCH receptors show reductions in feeding provoked by food cues in the absence of hunger [14]. Neuroimaging studies suggest that these circuits translate to humans. For example, the magnitude of milkshake-evoked response in the basolateral amygdala is positively associated with change in BMI over one year, but this effect is only observed in the sated and not in the hungry state [15]. Moreover, dynamic causal modeling analyses reveal interesting effects of internal state in amygdala-to-hypothalamus circuitry in humans. Specifically, when hungry, amygdala-to-hypothalamus communication is predominantly bidirectional. However, when sated, communication shifts toward unidirectional inputs from the amygdala to the hypothalamus, suggesting that the influence of the amygdala on hypothalamic feeding centers depends on state in humans as it does in animals [15].

Functioning prefrontal circuits are also required for the expression of cue-potentiated feeding in sated rodents. In their 2002 study, Petrovich et al. found that contralateral lesions of the amygdala and hypothalamus were sufficient to block cue-potentiated feeding, but not second-order conditioning previously shown to depend on amygdala-to-nucleus accumbens circuitry [11,16]. These data suggested that cue-potentiated feeding is unlikely conveyed by indirect projections from the amygdala to the hypothalamus through the nucleus accumbens. Yet it remained unclear whether the critical amygdala-to-hypothalamus communication was direct, indirect via other brain regions, or a combination of both. To test this, the authors performed a follow-up study that combined anatomical tract-tracing and immediate early gene methods [17]. In particular, they investigated brain regions projecting to the lateral hypothalamus that are activated by conditioned food cues which stimulate consumption. Neurons in the basolateral amygdala, basomedial amygdala, and orbitomedial prefrontal cortex – but not in the central amygdala or nucleus accumbens – were selectively activated by the food cue [17]. Subsequent lesioning of the ventromedial prefrontal cortex impaired cue-driven eating in rats without impacting their baseline food consumption or body weight during cue association training [18]. Collectively, this evidence favors mediation of cue-potentiated feeding in the sated state by amygdalar-prefrontal-hypothalamic circuitry without involvement of the striatum.

To summarize, Weingarten’s observations in 1983 provided the first experimental proof that an initially neutral sensory cue experienced concurrently with food consumption in a hungry state could be conditioned to cause eating during satiety. This experiment paved the way for later work to identify the neural circuits underlying cue-driven eating and the eventual translation to humans. Although the effect of obesity or obesity proneness in rodents remains to be studied, accumulating work in humans continues to highlight the importance of this circuitry and cue-potentiated feeding in overeating and obesity risk within an environment laden with food cues. To date, preclinical studies have largely focused on dopaminergic and opioidergic striatal circuits in obesity and food addiction-like behaviors [19,20]. The studies fueled by Weingarten’s seminal paper suggest that the independent role of amygdalar-prefrontal-hypothalamic circuitry in weight gain susceptibility warrants further investigation.

References

1. Schachter, S. (1968). Obesity and Eating. Science 161, 751–756. 10.1126/science.161.3843.751.

2. Weingarten, H.P. (1983). Conditioned cues elicit feeding in sated rats: a role for learning in meal initiation. Science 220, 431–433. 10.1126/science.6836286.

3. Jansen, A., Havermans, R.C., and Nederkoorn, C. (2011). Cued Overeating. In Handbook of Behavior, Food and Nutrition, V. R. Preedy, R. R. Watson, and C. R. Martin, eds. (Springer), pp. 1431–1443. 10.1007/978-0-387-92271-3_92.

4. Boswell, R.G., and Kober, H. (2016). Food cue reactivity and craving predict eating and weight gain: a meta-analytic review. Obes Rev 17, 159–177. 10.1111/obr.12354.

5. Jansen, A., Theunissen, N., Slechten, K., Nederkoorn, C., Boon, B., Mulkens, S., and Roefs, A. (2003). Overweight children overeat after exposure to food cues. Eating Behaviors 4, 197–209. 10.1016/S1471-0153(03)00011-4.

6. Hendrikse, J.J., Cachia, R.L., Kothe, E.J., McPhie, S., Skouteris, H., and Hayden, M.J. (2015). Attentional biases for food cues in overweight and individuals with obesity: a systematic review of the literature. Obesity Reviews 16, 424–432. 10.1111/obr.12265.

7. Ferriday, D., and Brunstrom, J.M. (2011). ‘I just can’t help myself’: effects of food-cue exposure in overweight and lean individuals. International Journal of Obesity 35, 142–149. 10.1038/ijo.2010.117.

8. Gilhooly, C.H., Das, S.K., Golden, J.K., McCrory, M.A., Dallal, G.E., Saltzman, E., Kramer, F.M., and Roberts, S.B. (2007). Food cravings and energy regulation: the characteristics of craved foods and their relationship with eating behaviors and weight change during 6 months of dietary energy restriction. Int J Obes 31, 1849–1858. 10.1038/sj.ijo.0803672.

9. Fedoroff, I.D.C., Polivy, J., and Herman, C.P. (1997). The Effect of Pre-exposure to Food Cues on the Eating Behavior of Restrained and Unrestrained Eaters. Appetite 28, 33–47. 10.1006/appe.1996.0057.

10. Perszyk, E.E., Davis, X.S., Djordjevic, J., Jones-Gotman, M., Trinh, J., Hutelin, Z., Veldhuizen, M.G., Koban, L., Wager, T.D., Kober, H., Small, D.M. (2023). Odor imagery but not perception drives risk for food cue reactivity and increased adiposity. 2023.02.06.527292. 10.1101/2023.02.06.527292.

11. Petrovich, G.D., Setlow, B., Holland, P.C., and Gallagher, M. (2002). Amygdalo-Hypothalamic Circuit Allows Learned Cues to Override Satiety and Promote Eating. J. Neurosci. 22, 8748–8753. 10.1523/JNEUROSCI.22-19-08748.2002.

12. Bittencourt, J.C. (2011). Anatomical organization of the melanin-concentrating hormone peptide family in the mammalian brain. General and Comparative Endocrinology 172, 185–197. 10.1016/j.ygcen.2011.03.028.

13. Bittencourt, J.C., Presse, F., Arias, C., Peto, C., Vaughan, J., Nahon, J.-L., Vale, W., and Sawchenko, P.E. (1992). The melanin-concentrating hormone system of the rat brain: An immuno- and hybridization histochemical characterization. Journal of Comparative Neurology 319, 218–245. 10.1002/cne.903190204.

14. Sherwood, A., Holland, P.C., Adamantidis, A., and Johnson, A.W. (2015). Deletion of Melanin Concentrating Hormone Receptor-1 disrupts overeating in the presence of food cues. Physiology & Behavior 152, 402–407. 10.1016/j.physbeh.2015.05.037.

15. Sun, X., Kroemer, N.B., Veldhuizen, M.G., Babbs, A.E., Araujo, I.E. de, Gitelman, D.R., Sherwin, R.S., Sinha, R., and Small, D.M. (2015). Basolateral Amygdala Response to Food Cues in the Absence of Hunger Is Associated with Weight Gain Susceptibility. J. Neurosci. 35, 7964–7976. 10.1523/JNEUROSCI.3884-14.2015.

16. Setlow, B., Holland, P.C., and Gallagher, M. (2002). Disconnection of the basolateral amygdala complex and nucleus accumbens impairs appetitive Pavlovian second-order conditioned responses. Behavioral Neuroscience 116, 267–275. 10.1037/0735-7044.116.2.267.

17. Petrovich, G.D., Holland, P.C., and Gallagher, M. (2005). Amygdalar and Prefrontal Pathways to the Lateral Hypothalamus Are Activated by a Learned Cue That Stimulates Eating. J. Neurosci. 25, 8295–8302. 10.1523/JNEUROSCI.2480-05.2005.

18. Petrovich, G.D., Ross, C.A., Holland, P.C., and Gallagher, M. (2007). Medial Prefrontal Cortex Is Necessary for an Appetitive Contextual Conditioned Stimulus to Promote Eating in Sated Rats. J. Neurosci. 27, 6436–6441. 10.1523/JNEUROSCI.5001-06.2007.

19. Saper, C.B., Chou, T.C., and Elmquist, J.K. (2002). The Need to Feed: Homeostatic and Hedonic Control of Eating. Neuron 36, 199–211. 10.1016/S0896-6273(02)00969-8.

20. Kenny, P.J. (2011). Common cellular and molecular mechanisms in obesity and drug addiction. Nat Rev Neurosci 12, 638–651. 10.1038/nrn3105.