Food anticipatory hormonal responses: a systematic review of animal and human studies. Aleksandrina Skvortsova et al. Neuroscience & Biobehavioral Reviews, April 1 2021. https://doi.org/10.1016/j.neubiorev.2021.03.030
Highlights
• Cues associated with food trigger release of homeostasis regulating hormones.
• Food anticipatory hormonal responses are consistently found in animals and humans.
• These responses regulate hunger, prevent hypoglycemia, and improve metabolism.
• Food anticipatory hormonal responses are largely learned phenomena.
• Food anticipatory hormonal activity is impaired in eating and metabolic disorders.
Abstract: Food anticipatory hormonal responses (cephalic responses) are proactive physiological processes, that allow animals to prepare for food ingestion by modulating their hormonal levels in response to food cues. This process is important for digesting food, metabolizing nutrients and maintaining glucose levels within homeostasis. In this systematic review, we summarize the evidence from animal and human research on cephalic responses. Thirty-six animal and fifty-three human studies were included. The majority (88%) of studies demonstrated that hormonal levels are changed in response to cues previously associated with food intake, such as feeding time, smell, and sight of food. Most evidence comes from studies on insulin, ghrelin, pancreatic polypeptide, glucagon, and c-peptide. Moreover, impaired cephalic responses were found in disorders related to metabolism and food intake such as diabetes, pancreatic insufficiency, obesity, and eating disorders, which opens discussions about the etiological mechanisms of these disorders as well as on potential therapeutic opportunities.
Keywords: anticipatory hormone releasecephalic responsesfood
4. Discussion
There is a large body of research demonstrating that cephalized organisms (ranging from insects to mammals) anticipate food intake via environmental cues with the aim to maintain homeostasis by adjusting their hormonal levels. Anticipatory hormonal changes, so-called cephalic responses, were found in a wide range of hormones but most evidence exists for insulin, ghrelin, pancreatic polypeptide, glucagon, and c-peptide. Animal research is very consistent in finding anticipatory hormonal changes with almost all studies demonstrating significant results, while the majority of human research also finds anticipatory hormonal changes. There is also some evidence for impaired cephalic responses in several metabolic and eating disorders in comparison to healthy participants, although more research is needed. Taken together, the current systematic review shows that the release of a wide range of hormones happens prior to food consumption both in animals and humans and it plays an important role in preparing the organisms for the food ingestion.
The direction of the hormonal changes in response to food anticipation mirrors the hormonal changes in response to food digestion: insulin, ghrelin, glucagon, pancreatic polypeptide, gastrin, and c-peptide levels increase. These processes indicate early adaptive preparation of the organism to the food digestion. The only hormone that does not have a direct relation to metabolism, but was repeatedly investigated in the context of food anticipation, is cortisol (corticosterone in rodents). Cortisol and corticosterone increase were found during food anticipation (Ott et al., 2012) (Coover et al., 1984; Moberg et al., 1975). Moreover, levels of cortisol and corticosterone dropped rapidly after food consumption (Moberg et al., 1975). Speculatively, food anticipation triggers a stress response in the organism and, therefore, leads to cortisol release. Possibly, an increase in stress hormones is necessary to increase alertness in animals in anticipation of food (Feillet, 2010).
It is still not entirely known to what extend cephalic responses are triggered by classical conditioning and whether some of them can be inborn. The only study included in this review that investigated this question directly, (Bernstein and Woods, 1980) demonstrated that cephalic insulin release in response to sweet taste is absent in newborn rat pups but already present in 21-22 day-old rats. Also, multiple experiments in both animals and humans showed that cephalic responses are present in subjects who followed fixed eating pattern in contrast to subjects who were fed ad libitum or without a fixed pattern (Holmes et al., 1989; Moberg et al., 1975; Woods et al., 1977). Therefore, evidence points that cephalic responses are to a large extent dependent on classical conditioning. That is, organisms learn that certain stimuli predict the availability of the food, and respond to these stimuli with cephalic hormones release to prepare the body for food consumption. Cephalic responses have been shown to be elicited not only by the cues that naturalistically predict food (such as time of eating/feeding or smell of food) but also by conditioning to neutral stimuli such as the sound of a door opening (Strubbe, 1992), or a mixed stimulus of a sound and a light (Storlien, 1985).
In addition to memory processes, such innate component, as circadian modulation, seems to affect food anticipatory hormonal responses. One study included in this review investigated a role of circadian clock in the cephalic responses (Patton et al., 2014). Patton and colleagues (2014) demonstrated food anticipatory corticosterone and ghrelin release to be more pronounced in the mice that were fed during the dark phase, than in the mice fed during the light phase. Mice are nocturnal animals, and free fed mice tend to exhibit food anticipatory activity during night. Therefore, the food anticipatory activity seems to be enhanced in the cases when feeding schedule corresponds to the light-dark rhythms. In case when there is a mismatch between dark-light cycle and the feeding pattern, for example, if food is given only in the usual sleep phase, the food anticipatory hormonal responses still appear (Feillet, 2010; Mistlberger, 1994) but might be of a smaller magnitude than in cases when there is no such a mismatch (Patton et al., 2014).
Another not well understood question about the cephalic responses, is what stimuli trigger it and in what cases. There is a discrepancy between animal and human research regarding the question whether mere taste elicits anticipatory hormone release or consumption of whole organoleptic stimulation of foods is needed. A large number of human studies failed to find anticipatory insulin release in response to a sweet taste of a nun-nutritive or low caloric substance alone (Abdallah et al., 1997; Bruce et al., 1987; Cedernaes et al., 2016; Härtel et al., 1993; Morricone et al., 2000; Smeets et al., 2005; Teff et al., 1995). At the same time, the response was found in the large number of studies that used sham feeding with whole foods (Buysschaert et al., 1985; Glasbrenner et al., 1995; Goldschmiedt et al., 1990; Teff et al., 1995, 1993, 1991). Moreover, a number of studies found that there are responders and non-responders to the taste stimulation (Bellisle et al., 1985; Dhillon et al., 2017; Teff et al., 1991). This might indicate that a combination of tactile, olfactory and taste stimulation provided by whole foods is needed to elicit a reliable cephalic response in humans. At the same time, it seems not to be the case in animals. All animal studies included into this review found cephalic hormone release to the sweet taste alone. Various reasons can explain this discrepancy between animal and human research. For example, cognitive factors play an important role in food anticipation in humans. Also, most people have previous experience with tasting various sweeteners that might affect their cephalic responses, while laboratory animals usually follow standard diets and are naïve to low caloric sweeteners.
Underlying neural mechanisms of the cephalic hormonal responses were investigated only in a few animal and human studies. It is proposed that in response to the food cues, the brain initiates insulin secretion by directing the signal through the vagus nerve to the pancreas (Woods, 1991). Animal research demonstrated that vagotomy, a surgical removal of a part of vagus nerve, leads to the disappearance of cephalic responses (Bernstein and Woods, 1980; Herath et al., 1999; Storlien, 1985). Human research confirms these results: administration of atropine, a drug that opposes the actions of the vagus nerve by blocking the acetylcholine receptors, was shown to abolish cephalic insulin (Sjöström et al., 1980) and pancreatic polypeptide release (Veedfald et al., 2016). Another substrate that has been proposed to underlie cephalic responses is the ventromedial nucleus of the hypothalamus, a brain area that is linked to satiety (Kurrasch et al., 2007). Animals with lesions of this area exhibit no cephalic responses to sweet taste and a complex stimulus previously associated with food (Berthoud et al., 1980a,b; Storlien, 1985). Another human study demonstrated that the upper hypothalamus might play a role in cephalic hormone release but only when stimulated by both sweet taste and high energy content: they showed that the injection of glucose, and not aspartame (sweet non-caloric taste) or maltodextrin (non-sweet carbohydrate) leads to significant decreases in the activity in the upper hypothalamus (Smeets et al., 2005).
Interestingly, human research shows an important role of cognition in food anticipatory hormonal releases. For example, a mere discussion about food triggered insulin release (Feldman and Richardson, 1986) and expected food palatability influenced cephalic responses (Rigamonti et al., 2015). Moreover, Crum and colleagues (Crum et al., 2011) demonstrated that the decrease of ghrelin levels after food consumption was larger in magnitude in participants who thought that they had consumed a high caloric shake in comparison to the participants who thought that the shake was low caloric (in reality it was the same shake). Cognition might also explain the discrepancy in the results between the studies that measured cephalic responses in humans to food consumption and sham feeding. While animal research found that both of these methods are very successful in eliciting anticipatory hormone release, a number of human studies that involved sham feeding, found no such responses. Participants in the studies with sham feeding knew that they would have to discharge the consumed food, and possibly, this knowledge might have affected their anticipatory hormonal responses. These studies point to the importance of conscious expectations in this physiological process: mere thoughts about food that people have might affect their hormonal responses. Additionally, the role of cognitive capacities in food anticipatory responses have never been studied before. For instance, no research in this topic have been done in infants or in people with cognitive disabilities. Future research should look at how cognition about food and cognitive capacities influence learned food anticipatory responses.
Studies that investigated cephalic responses in clinical populations demonstrate that anticipatory hormonal responses were affected in patients with diabetes with cardiac autonomic neuropathy (Buysschaert et al., 1985; Glasbrenner et al., 1995), obesity (Brede et al., 2017; Johnson and Wildman, 1983; Osuna et al., 1986; Sjöström et al., 1980), eating disorders (Broberg and Bernstein, 1989; Monteleone et al., 2010, 2008; Moyer et al., 1993), pancreatic insufficiency (Wøjdemann et al., 2000), and kidney and pancreas transplantation (Secchi et al., 1995). However, the number of studies that included clinical populations is limited. It remains unknown whether disturbed cephalic responses play a causal role in the development of some of these disorders, or, alternatively, are consequences of them. Future studies should investigate the role of cephalic responses in the development of metabolic disorders and the possibility of using cephalic responses as a diagnostic tool for some of these disorders.
Several limitations of the studies included into the current review should be mentioned. First of all, the risk of bias assessment demonstrated that the majority of the studies included in this review did not report enough information to make it possible to objectively assess the bias. Particularly it applies to the animal research that did not provide information regarding the method of assigning animals to different conditions and blinding of the personnel. Similar problems, but to a lesser extent, are present in human studies. Only one study preregistration was available in open access and the majority of the studies did not report whether the analysis of outcome was done by blinded personnel. Moreover, none of the studies described whether the statistical power calculation had been done prior to the study what makes it difficult to interpret null findings. Furthermore, we found that while almost all animal studies found cephalic responses, human research varied more with respect to the results. This phenomenon can be explained by several reasons. Firstly, a larger publication bias might exist in animal research. It has been recently demonstrated that animal studies with null-findings are often not published creating a large bias in the animal literature (ter Riet et al., 2012). Secondly, additional factors might play a role in humans that are presumably less important in animals, for example, cognition. Most of the human studies, however, did not take into considerations such factors, such as expectation of participants, even though cognitive factors have been shown to affect cephalic responses (Crum et al., 2011; Feldman and Richardson, 1986). Ignoring these potential confounding factors, might have led to the occasional null findings in human studies. Most of the animal and human research has been done either in males or in mixed-sex samples. Only one study included in this review looked at sex differences: they demonstrated that anticipatory ghrelin release peaks at different times in male and female mice and also in orchidectomized mice. Sex differences have been also found in glucose and lipid metabolism (Gur et al., 1995), which may potentially also affect anticipatory hormonal responses. Therefore, it is essential that future research focus on potential sex differences in the food anticipatory hormone release. Furthermore, many different methods and protocols were used for measuring anticipatory hormonal responses, and almost no study compared different methods. These differences complicate interpreting null-findings of some of the studies. For example, several studies that involved sham feedings found no cephalic insulin release (Crystal and Teff, 2006; Teff et al., 1995), however, as every study used a different procedure of sham feeding (different foods, various times of chewing, various moments of sample collections), it remains unknown whether these null findings can be explained by the protocol used or whether cephalic insulin release does not occur in all cases.
Better understanding of cephalic hormonal responses brings several clinical possibilities. First, consumption of artificial low-caloric or non-nutritional sweeteners increases in modern society as these sweeteners are often added to common beverages and foods. It is still poorly understood how such discrepancy between the sweet taste and a low nutritional content can affect cephalic responses and whether it plays a role in the development of obesity and metabolic disorders. Moreover, the evidence from the current review indicates that cephalic responses might be affected in patients with metabolic disorders, however, the number of studies on this topic is limited. For example, it is unknown how impairment of cephalic responses progresses from obesity to metabolic syndrome and diabetes type 2. Possibly, measuring cephalic responses might be used as a predictive tool for the development of metabolic disorders.
The present review confirmed that there is a large body of literature supporting the existence of food anticipatory hormonal release. Moreover, there is some preliminary evidence at impairment of anticipatory hormonal responses in a range of disorders related to metabolism and food intake. More research is needed to understand the role of such impairments in cephalic responses and possibility to use cephalic responses as a predictor for the development of metabolic disorders.