Energy intake and obesity: ingestive frequency outweighs portion size.

PHB-10215; No of Pages 9 Physiology & Behavior xxx (2013) xxx–xxx

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Physiology & Behavior journal homepage: www.elsevier.com/locate/phb

Review

Energy intake and obesity: Ingestive frequency outweighs portion size Richard Mattes ⁎ Purdue University, Department of Nutrition Science, West Lafayette, IN, United States

H I G H L I G H T S • • • •

Ingestive frequency and portion sizes are not balancing to sustain stable body weight Different mechanisms drive ingestive frequency and portion size Physiological and behavioral factors influence ingestive frequency and portion size Ingestive frequency may contribute more to positive energy balance than portion size

a r t i c l e

i n f o

Article history: Received 2 August 2013 Accepted 18 November 2013 Available online xxxx Keywords: Portion size Eating frequency Obesity Appetite Food intake Energy intake

a b s t r a c t Energy intake is a function of the quantity of energy consumed per ingestive event and the number of these events. The marked increase of energy intake and body weight over the past 35 years indicates that there has been poor precision in the reciprocity of these two facets of intake. With recent study of the associations between gut “satiation” peptides and energy intake, there has been an emphasis on the contribution of portion size to positive energy balance. However, this orientation may not appropriately weight the contribution of ingestive frequency. Gut peptides are not purely satiation factors and metabolic and environmental cues may more strongly guide the onset and number of ingestive events. Evidence is presented that while both portion size and ingestive frequency have increased in the population, the latter may be more problematic for weight gain. The magnitude and time course of increments in ingestive frequency map better onto energy intake and BMI trends than changes of portion size. This may occur, in part, because dietary compensation and thermogenic effects are weaker for increases in ingestive frequency than portion size. Though not to the exclusion of consideration of portion size effects, improved weight management may be achieved with greater attention to the drivers of eating and drinking frequency. © 2013 Elsevier Inc. All rights reserved.

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . 1.1. Portion size trends . . . . . . . . . . . . . . . . 1.1.1. Portion size and appetite . . . . . . . . . 1.1.2. Portion size and energy intake . . . . . . . 1.1.3. Portion size and BMI . . . . . . . . . . . 1.2. Ingestive frequency trends . . . . . . . . . . . . . 1.2.1. Ingestive frequency and appetite . . . . . . 1.2.2. Ingestive frequency and intake . . . . . . . 1.2.3. Ingestive frequency and BMI . . . . . . . . 2. Biological and environmental influences on ingestive behavior 2.1. Metabolic modulation of ingestive frequency . . . . 2.2. Gut biology and modulation of portion size . . . . . 2.3. Environmental modulation of portion . . . . . . . . 2.4. Environmental modulation of ingestive frequency . . 3. Is portion size or ingestive frequency a bigger problem? . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Tel.: +1 7654940662. E-mail address: [email protected]. 0031-9384/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.physbeh.2013.11.012

Please cite this article as: Mattes R, Energy intake and obesity: Ingestive frequency outweighs portion size, Physiol Behav (2013), http:// dx.doi.org/10.1016/j.physbeh.2013.11.012

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R. Mattes / Physiology & Behavior xxx (2013) xxx–xxx

1. Introduction Eating patterns vary widely between individuals and populations. Energy intake can be parsed evenly across the day or disproportionately to selected times of the day and derive from varying numbers of ingestive (eating and drinking) events. Documented and hypothesized health and performance implications have been attributed to different patterns, such as moderated lipemic and glycemic responses with increased ingestive events of limited energy content [1,2], optimized protein synthesis with an even distribution of protein intake over the day [3] and better cognitive function after a morning meal, but a possible reduction after a midday meal with both of these responses modified by customary dietary pattern [4]. However, multiple trials have now confirmed that total energy intake, relative to expenditure, is the ultimate determinant of body weight [5,6]. An individual's total energy intake is determined by the number of their ingestive events and the energy consumed per ingestive event. These two facets of intake are governed by different mechanisms, but under homeostatic models based on either active regulation or more passive accommodation [7–9], they are assumed to interact reciprocally. With stable body weight or composition (the predominance of either remains to be determined), variation in one facet is offset by an adjustment of the other. The effects of cholecystokinin (CCK) administration or augmentation via central insulin infusion is a case in point. In rodents, these conditions lead to a marked decrease of portion size, but no change in energy intake due to a compensatory increase in eating frequency that results in relatively precise energy balance [10]. Similar findings are noted in baboons where central administration of insulin augments CCK activity and suppresses portion size, but not total energy intake [11]. CCK also reduces portion size in humans [12], but with chronic administration, it does not reduce daily energy intake or promote body weight loss [13]. Whether the findings in humans actually reflect a behavioral change towards greater ingestive frequency or decreased reactivity to CCK is not established. Nevertheless, there are numerous examples of a trade-off between ingestive frequency and portion size from the human literature (e.g., [14–17]). Over the past 35 years, there has been a sharp increase in the body weight and adiposity of the population [18,19]. This implicates a lack or loss of precise reciprocity. The aim of this review is to evaluate the roles of ingestive frequency and portion size in population trends of body weight and composition. Clarification of terminology will facilitate the discussion. We use ingestive frequency rather than the more common phrase, “eating frequency,” because beverage consumption contributes approximately 20% of energy to the diet [20] and “ingestive” is intended to be inclusive of eating and drinking. We refer to portion size rather than the more frequently used, “meal size,” expressed in energy value. This is because there is no widely accepted definition of a meal or snack, yet consumer defined snacking contributes about 25% of daily energy intake [21]. Hunger refers to the sensations that prompt an ingestive event and fullness is the term for sensations that terminate an ingestive event. To address the topic, we begin with a review of trends in portion size and ingestive frequency and their relationships to appetite, energy intake and body weight. We follow with a critical appraisal of the mechanisms governing portion size and ingestive frequency and conclude with a consideration of which may be the stronger driver of positive energy balance and hence, an important target for interventions to manage body weight. 1.1. Portion size trends There is a strong consensus that portion sizes have increased; general agreement that this has led to increased energy intake, and mixed evidence that this has resulted in increased body weight or BMI in the population. Consumers consider value for money an important determinant of food choice, and larger portion sizes are believed to deliver better value [22]. Hence, there is demand for larger portions, and this is being

met by the food industry. Based on Continuing Survey of Food Intakes by Individuals (CSFII) data, portion sizes increased for 23 of the 107 most commonly eaten items in 1994–6 compared to 1989–91 [23]. Decreases were noted for only 10 items (4 of which were margarines or mayonnaise). Between 1977 and 1996, foods with the greatest increases in portion size contributed 18.1% of energy to the diet during 1977–1978, but increased their representation to 27.7% in the 1994–1996 period in adults [24]. Portion sizes then plateaued between 1994–1998 and 2003–2006 [25]. Among children, portion sizes increased across all food and beverage categories (except desserts) between 1977–1978 and 2003–2006. Interestingly, the trend for greater portion sizes was comparable in magnitude for foods prepared and consumed within the home as well as to items purchased and ingested elsewhere. This suggests that the change in cultural norms is internalized and not just a reflection of constraints on availability of smaller portion options. Indeed, the largest portion sizes for desserts, hamburgers and cheeseburgers were reported in homes and recent evidence indicates that when children are permitted to serve themselves, their portion sizes are not smaller than when they are served their food [26]. The increase in portion sizes may have originated in the 1970s and has continued to grow since that time so that portion sizes for ready-to-eat items are generally 2–8 fold higher than standard US Department of Agriculture and US Food and Drug Administration servings [27]. 1.1.1. Portion size and appetite Although it is intuitive that larger portion sizes should lead to greater fullness ratings, this is not a robust finding. Preload studies using visual analog scale (VAS) ratings yield mixed outcomes when ratings are obtained immediately before and after an ingestive event [28] or are tracked for several hours following an ingestive event [29]. Some work indicates that when individuals are not alerted to varying portion sizes or components within meals, they may not detect differences even as great as a doubling of their customary portion [30]. Additionally, when visual cues are purposefully minimized and intake is not constrained, energy consumption may increase markedly while consumers report no difference in portion size [31] and manipulating just information about portion size has no impact on ratings of fullness or intake [32]. Taken together, the evidence is not strong that individuals are cognitively sensitive to modest variations in portion size; that their self-reported fullness tracks energy intake due to variations in portion size; or that increases in fullness achieved through manipulation of portion size result in less energy intake. 1.1.2. Portion size and energy intake An increase in portion size is problematic for weight management if it results in an increment in energy intake. This may not occur if the full portion is not consumed and/or if the larger portion elicits precise dietary compensation. Some acute, controlled-feeding trials indicate that presentation of larger portions leads to greater energy intake in children [33–35] and adults [34,36]. Even when judges are able to correctly identify graded portion sizes and recognize that some are larger than their customary portion, this does not necessarily prevent energy intake exceeding customary levels when confronted with large portions [28]. However, other investigators report no differential intake with presentation of varying portion sizes [37] or a statistically significant direct effect that is very small in absolute size so of uncertain nutritional importance [38]. Comparable studies in children [39] and adults [40] document strong compensatory dietary responses across meals. In children, provision of meals and snacks over a day revealed large individual coefficients of variability at any single eating event that ranged from about 10 to 95% (mean estimated from figure of about 35%), but ranged only from about 2 to 18% (estimated mean of 10%) when summed over the day. In a study on adults, free-living intake was assessed at breakfast, mid-morning, lunch, mid-afternoon, dinner and evening for a 7 day period. Again variability was high at each eating event with a range of about 5–275% (mean of 68–158% over the



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7 days), but reduced to a range of about 10–60% (mean of about 35%) summed over the day. Thus, the meal–day variability ratio was approximately 3.0:1 in the children and 3.8:1 in the adults. This pattern was attributed to compensation as correlation coefficients between all 35 possible sequential eating events (5 eating events over the day for 7 days) were negative. The responses were similar in lean and obese individuals. These later observations raise questions about attributing risk for weight gain to particular ingestive occasions (e.g., fast food meals). If they are high in energy, but this is offset by a planned or spontaneous reduction of energy intake earlier or later in the day, their contribution to positive energy balance may be limited. Compensation may also occur within an ingestive event where increased intake from one food is offset by decreased consumption of others resulting in a relatively stable level of energy intake over particular ingestive events [41]. Most controlled feeding trials that entail a manipulation of portion size are preload studies limited to a day or less. However, a few trials of 2 days to 2 months have been reported. They generally indicate that presentation of larger portions results in greater energy intake. In a two-day cross-over trial [42], providing portions that were 50% and 100% greater than a baseline diet led to a dose–response increment in energy intake. With the 50% increase condition, energy intake was 16% higher (120% of estimated energy need) and with the 100% increase, intake was 26% higher (130% of estimated need). In a four-day, cross-over trial in a residential setting, 60 foods were presented in standard portions or portions that ranged from the same to twice the size [43]. Energy intake rose by 17% in males and 10% in females and was sustained for the treatment period. An eleven-day cross-over trial revealed that a 50% increase in portion sizes led to a 25% increment in energy intake in females and 14% rise in males that was sustained over the treatment period. In each of these trials, participants were able to eat/drink ad libitum, but food choices were fixed and during the intervention periods, essentially all foods were presented in larger portions. Thus, while experimentally understandable, some mechanisms of compensation available to free-living individuals were not options to study participants. Additionally, all foods were prepared and provided free-of-charge. So findings must be interpreted cautiously. However, these findings are supported by a more naturalistic four week cross-over trial of free-living individuals who were only provided box lunches in 767 kcal and 1528 kcal versions [44]. The balance of the diet was not controlled. Based on self-report and unannounced 24-hour telephone dietary recalls, energy intake of the lunch meal was 43% higher and daily energy intake was 15% higher with the large portion. The increment of intake was stable over the trial. Collectively, these limited findings suggest that exposure to portions that are 50–100% greater than customary values results in an approximately 10–25% increment in energy intake. Thus, there is strong compensation even where some options for compensation are not available to study participants. Under free-living conditions, an important caveat to consider when evaluating portion size and energy intake, is waste. There are data suggesting that waste is directly related with portion size [45]. This would reduce the impact of larger portions on total energy intake. The amount of waste in the food system is underappreciated. Though not fully attributable to large portions, food waste has increased by roughly 50% since 1974 and equals more than 1400 kcal/person/day [46].

CSFII data. In one report, portion size was significantly associated with body weight in 1–2 year olds [16]. Another analysis of children aged 3–19 years of age revealed that portion size was positively associated with BMI percentiles only in 3–5 year olds and the portion size of snacks was only positively associated with BMI percentiles in 6–11 year olds [47]. In further analyses of plausible energy reporters, portion size was positively associated with BMI in boys 6–11 and boys and girls 12–19 years of age. There are reports of a positive association between portion size and obesity in adults, but the findings must be interpreted cautiously as portion size is often confounded by a higher energy density of the diet of the obese [48] or by under-reporting [49]. In sum, portion sizes have been increasing for a broad array of foods and beverages. In controlled studies, manipulations of portion size, whether detected or not, have limited impact on reported fullness. Acute and short term feeding trials suggest that marked increases in portion size result in only small increments of energy intake due to compensatory dietary responses. Consequently, the limited data on how this translates to changes of body weight or adiposity suggests that effects are not robust. There are no randomized controlled trials that would permit assignment of causality between long-term exposure to large portions and increments in body weight.

Much of the data on ingestive frequency is based on self-reports of consuming meals and snacks as defined by consumers. Snacking is used as a proxy for increased ingestive frequency. This has some limitations because it cannot be assumed that each snack constitutes an additional ingestive occurrence since meal skipping is also common [50–53]. Some differences in associations based on ingestive frequency and snacking with energy intake and BMI have been reported [54]. With these caveats, there are strong data supporting a trend for increased ingestive frequency in children, adolescents and adults over the past 35 years. Based on data from the NHANES and CSFII surveys, the prevalence of daily snacking increased from 74% in 1977–78 to 98% in 2003– 2006 among children [41]. This was associated with an increased energy intake of 168 kcal/day from snacks. Total energy intake increased by113 kcal/day between 1977 and 2006 and snacking represented 27% of total daily energy intake in 2006. At the time, the energy density of snacks decreased (children aged 2–6 years) or remained unchanged (7–19 year olds) in segments of the population. Similar trends occurred among adolescents. The percentage of daily snackers increased from 61% in 1977–78 to 83% in 2003–2006 [55]. The mean frequency of snacking increased from 1.0 to 1.7 occurrences per day. The percentage of adolescents consuming three or more snacks per day increased from 9 to 23% over this time. In 2003–6, snacks accounted for 23% of daily energy. The daily energy provided by snacks increased from 300 kcal in 1977–8 to 526 kcal in 2003–6. Among adults, snacking increased from 1.0 to 2.2 occurrences/day between 1977–8 and 2007–8 [56]. The proportion of adults who snack increased from 59% to 90%. Snacks now constitute about 24% of daily energy, but close to 30% of the population derives 30% or more of their energy from snacks. The absolute amount of energy from snacks is 421 kcal for women and 586 kcal for men.

1.1.3. Portion size and BMI If portion sizes have been increasing over time and are not fully compensated, an impact on weight would be predicted. The literature on portion size and body weight is largely comprised of short term controlled feeding trials and epidemiological analyses. In the four-week trial cited above [44] where only the midday meal was manipulated, the larger portion was associated with a 0.64 ± 1.16 kg weight gain whereas the change on the standard portion was 0.06 ± 1.03 kg. These weight changes were not significant over time or between test periods though statistical power was low. Mixed findings have been reported for infants, children and adolescents based on analyses of

1.2.1. Ingestive frequency and appetite The effects of ingestive frequency on appetitive ratings derive primarily from preload studies and short-term feeding trials. Generally, they reveal an insensitivity of appetitive sensations to ingestive frequency [57,58]. In some instances greater ingestive frequency was associated with lower fullness ratings [29]. In others, increased ingestive frequency had no effect on fullness, but raised hunger and desire to eat ratings [59]. A direct association between ingestive frequency and hunger is most apparent when ingestive frequency is restricted to only one or two occasions per day [60,61]. To the extent that snacking is the driver of variability in ingestive frequency, the weak association

1.2. Ingestive frequency trends


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between ingestive frequency and hunger or fullness ratings may reflect the multiple social/cultural influences on snacking patterns. Snacking is hypothesized to be less motivated by biological energy needs than meals [62,63] though, if true, a clear direct association between desire to eat ratings and snacking would be predicted and this has not emerged from the literature. 1.2.2. Ingestive frequency and intake There is a widely held view that increased ingestive frequency will moderate swings in hunger sensations and, as a result, energy intake. However, as noted above, the association between ingestive frequency and appetite is weak and the preponderance of evidence supports a direct association with energy intake. The large nationally representative epidemiological surveys reveal that higher snacking frequency is associated with greater energy intake among adolescents. Those who consumed four or more snacks per day had energy intakes roughly 50% higher than non-snackers [55,64]. Similarly, in adults, there is a direct relationship between snacking and daily energy intake. Those who consume four or more snacks per day consume approximately 50% more energy daily than non-snackers [56]. Similar findings were published based on CSFII data [65]. A positive association is also noted based only on analyses of ingestive frequency with data from the third NHANES [66]. Individuals eating six or more times per day consume approximately 75% more energy than those reporting eating only one or two times per day. A positive association is also reported from analyses of the Rancho Bernardo study [67], the Weight Loss Registry [68] and trials in European [69] and Asian populations [70]. The survey data are supported by some clinical trials [54,71], though evidence from acute feeding studies has also revealed no effect of two versus six ingestive events per day on energy intake [72]. In a tightly controlled cross-over design study where participants were provided 3 snacks per day plus meals or only meals for 9 days each, greater ingestive frequency did not lead to a rise in energy intake [73]. However, as the authors note, findings must be extrapolated cautiously as the times of eating occurrences and the energy density of all foods were fixed and this does not replicate naturalistic conditions. 1.2.3. Ingestive frequency and BMI Given the weak effects of ingestive frequency on appetite, and evidence from nationally representative surveys that ingestive frequency is positively associated with energy intake, it may be expected that ingestive frequency would be directly related to BMI. This issue has recently been reviewed [74]. Multiple studies report a positive association between snacking and body weight in children and adults (e.g., [71,75–78]). Further, increased ingestive frequency does not promote greater weight loss [79] and reduced ingestive frequency reportedly leads to lesser weight gain in 10–16 year old children, though not 6–11 year olds [80]. A notable trend for increased beverage-only ingestive occasions has occurred among children [20]; a trend that may be especially problematic for weight gain [74,81]. The interval between ingestive occasions in the US population has decreased by an hour to only 3.0 and 3.5 h in adults and children respectively [20]. However, equal numbers of studies reveal no association or an inverse association between ingestive frequency and BMI [74]. Of particular note, BMI does not change significantly with snacking frequency among adolescents [55,82] or adults based on NHANES [56] and CSFII [65] data which are nationally representative samples of the US population. Multiple explanations for these inconsistent associations have been posited. Among these are 1) effect inconsistencies across study populations (e.g., lean versus obese [83], types of foods consumed as snacks (e.g., [84]), and dieting status [85]); 2) insensitivity and/or bias of dietary data [86,87]; 3) failure to distinguish between planned and unplanned snacking [87]; and 4) true lack of causation, but snacking serves variably as a marker for healthier or less healthy lifestyles (e.g., [88,89]). The veracity of the inverse associations is of particular concern as they may reflect well known under-reporting effects. As noted in an

earlier review, under-reporting is directly related to self-reported ingestive frequency [86]. This can result in biased negative conclusions. Additionally, the association may reflect reverse causality where heavier individuals choose to skip ingestive occasions as a weight management approach. This again would lead to biased conclusions. In a more recent review of evidence pertaining to ingestive frequency and BMI [87], it was noted that when implausible energy intake reporters are omitted from analyses, some of the inverse relationships become nonsignificant or positive (e.g., [75,90,91]). Further, in an analysis of CSFII data, the finding of no significant association between eating frequency and BMI became positive when implausible reporters were omitted [87]. Taken together, there are strong data that ingestive frequency has increased. This has had limited impact on appetitive sensations and resulted in increased energy intake. The rise in energy intake has not translated into a consistent increase of body weight or adiposity, but this is likely masked by a number of confounding influences, especially under-reporting. 2. Biological and environmental influences on ingestive behavior Questions about whether portion size is a determinant of the subsequent interval before the next ingestive event or if the length of the preceding interval is a determinant of the size of an ingestive event are old and persistent. Some have argued that there is no meaningful association [92]. However, detailed assessments of the structure of feeding behavior in a variety of animal models reveal that the strength of such associations depends on the definition of meals [93,94]. Modeling that yields the most stable descriptor of observed feeding patterns, leads to the conclusion that each is predictive of the other. Studies of eating patterns in time-isolated humans indicate that there is a direct association between the energy content of an eating occurrence and the interval to the next eating occurrence [95,96]. An association between the pre-ingestive interval and energy intake at an eating occurrence is mixed with some work showing a non-significant association [95] and other work revealing a significant association [96,97]. The latter association has led some to argue that portion size is not a driver of the interval between ingestive occurrences [96] and others to note that if a meaningful relationship exists, it may be undermined by cultural determinants of the timing of ingestive events [62,95]; hence the need to heed both when attempting to understand total energy intake. 2.1. Metabolic modulation of ingestive frequency There is a common view that ingestive frequency is largely under environmental (i.e., non-biological) control while portion size is guided more by physiological processes [98]. However, it is our premise that this only reflects the current research emphasis on contributions of gut peptides to ingestive behavior. Eating and drinking in humans occurs as periodic events and early theories of ingestive behavior emphasized cues to initiate eating (e.g.,[99,100]) such as changes of concentrations of glucose, amino acids, glycogen, fatty acids, glycerol, metabolites of intermediary metabolism, oxidative state and/or thermogenesis. For example, blood glucose concentrations have long been posited as a signal for ingestive initiation by multiple mechanisms. Mayer proposed that hypothalamic detection of declines of plasma glucose triggered food seeking and the initiation of eating [101]. This was later modified to a scenario where just transient dips of glucose were the relevant signal to initiate an ingestive event [102,103]. Le Magnen and Devos [104] linked glucose to lipid metabolism proposing that high rates of lipolysis signaled a glucose deficit and need to eat. Russek's version of a glucostatic theory of hunger initially held that chemoreceptors in the gut activate sympathetic nerves resulting in hyperpolarization of hepatic glucoreceptors which then influence satiety responses [105]. This was later modified to suggest that glucose was



not the direct signal, instead it was some index of glucose metabolism [106]. While none of these theories have held sway [107], it may be premature to discount a system that entails a contribution of glucose or some aspect of its metabolism to ingestive frequency. In all scenarios, it is a control system for short-term feeding [108] rather than master regulator of body weight or composition. Some [103] human data reveal shorter inter-ingestive intervals with rapid, post-prandial excursions of blood sugar. However, euglycemic clamp studies in humans indicated that independent excursions of glucose or insulin do not alter appetitive sensations [109]. The lipostatic theory stemmed from early observations of the stability of body fat to total body weight of adults, evidence from ventromedial hypothalamic lesions suggesting ingestive behaviors reflected body fat regulation [110] and that the amount of lipid mobilized daily was proportional to the total fat content of the organism [108]. The lipostatic theory was viewed as a mechanism for longer-term body weight regulation [108]. It was expanded based, in part, on observations in rats that the inter-ingestive interval was related to the preceding portion size and that the inter-ingestive interval was longer during the day compared to night [111]. The circadian pattern was important because it was noted that fat intake increased while the respiratory quotient decreased at night, indicative of fat synthesis, and the reverse held during the day. This led to an interest in the controls of these circadian patterns of lipid intake and metabolism. Given the interplay between carbohydrate and fat metabolism, it was proposed that there is a gluco-sensitive hunger system that modulates lipid metabolism [108]. The primary endocrine driver was insulin. It not only stimulated the initiation of eating and shorter inter-ingestive intervals, but was also reflective of body fat stores so it helped with longer-term body weight regulation [100]. More recently, a direct action of lipid digestion on satiety has been reported. Lipid feeding leads to the release of oleoylethanolamide (OEA) in the gut which decreases ingestive frequency [112]. The aminostatic theory, first proposed by Mellinkoff et al. [113] showed an inverse association between administered amino acids and hunger. A good deal of research in this area has focused on the contribution of protein to serotonin synthesis and activity since this neurotransmitter inhibits feeding. Microstructure of feeding studies indicate that manipulations of serotonin alter portion size and ingestive rate [114]. There is only limited evidence for effects on ingestive frequency [115]. However, human data show an increased delay to the onset of the next ingestive request with protein compared to carbohydrate or fat [116]. Similar findings were not reported based on diet records [117]. Additionally, energy intake at a challenge ingestive event provided at a fixed time after a high protein versus a high fat load was comparable and similar to a no load trial [118]. Further, protein provided to adults at three time points after an ingestive event (i.e., when they are in a sated state) failed to alter the inter-ingestive interval [116]. The important commonality of these theories is that the salience of the particular signaling molecules grew over the post-prandial period and theoretically primarily influenced ingestive initiation. Thus, they were determinants of ingestive intervals. However, due, in part, to the failure of these systems to fully explain ingestive behavior and advances in understanding of feeding-related gut physiology, the emphasis shifted to a focus on signaling systems modulating portion size [119] and hence, an emphasis on ingestive event termination; commonly defined as satiation. The shift occurred in the mid-1970s with the initial discovery of CCK and was expanded with identification of numerous additional gut peptides with putative appetitive effects. 2.2. Gut biology and modulation of portion size Nearly all identified gut peptides associated with appetite are considered satiation factors; ghrelin is a notable exception [120,121]. While much has been learned about these hormones over the past three decades, translation of this knowledge to feeding and weight management has been limited [122]. This is due not only to many issues

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such as complications with their administration, development of tolerance and experience of undesired side-effects, but also to limited evidence of their efficacy in humans. It is tempting to propose that this stems from the fact that, like ingestive frequency, portion size represents only half of the input for energy intake so their contribution constitutes an incomplete picture. However, it may be inaccurate to classify these gut peptides just as satiation factors. Effects on ingestive frequency are also reported. CCK is perhaps the most cited example of a satiation factor. It is released at meal onset and concentrations are independent of body fat suggesting that it is a short-term effector of fullness. Its administration reduces portion size [123,124] and disruption of CCK signaling leads to increased portion size [125]. However, administration of the CCK antagonist, camostat, also lengthens the interingestive interval [126]. There are both neural and nutritive triggers for GLP-1 secretion [127]. The response is biphasic and not mediated by body fat state. Presumably, the neural component is responsible for its initial rise which occurs within 15–30 min of ingestion onset. Nutrient induction leads to a sustained secretion starting about 60–90 min after ingestive initiation [127,128]. For the latter, there may be a 400–550 kcal threshold for release, so smaller eating events (snacks) may not effectively stimulate GLP-1 release [129,130]. Though commonly characterized as a satiation factor, it also modulates ingestive frequency [131]. Additionally, GLP-1 is a potent incretin, so it may alter appetite through insulin which is a satiety factor. PYY is secreted within 15 min of ingestive initiation and remains elevated for many hours after an ingestive event [132]. Due to its kinetics, it is most appropriately considered a satiation and satiety hormone; decreasing portion size and extending the inter-ingestive interval [133,134]. However, convincing documentation of both these outcomes through microstructure of feeding analyses is lacking in humans. The most prevalent view is that leptin exerts its anorectic effect through a reduction of portion size with limited effect on ingestive frequency (e.g.,[135,136]). However, there are a number of reports that leptin either reduces ingestive frequency with little effect on portion size [137] or reduces both ingestive frequency and portion size [138]. These discrepant responses likely reflect methodological differences in dose administered, site of infusion and definition of ingestive events [93]. In a more recent, rigorous, dose–response trial, findings indicated that the predominant action of centrally administered leptin is to reduce ingestive frequency [93]. Human data also support an effect on ingestive frequency [63]. Although leptin concentrations reflect body fat stores, concentrations also vary with short term shifts of energy balance [139], including intervals between ingestive events [140,141]. Even in rodent studies where the primary action was reported to entail reduced portion size, it was noted that there was no offsetting shift in ingestive frequency suggesting that leptin diminished hunger [142]. Similarly, amylin not only reduces portion size but also fails to elicit a reciprocal effect on ingestive frequency indicating that it also diminishes hunger [119,143]. Ghrelin is widely believed to promote hunger leading to ingestion. In rats, it reduces the time to initiation of ingestion and increases ingestive events with lesser effects on portion size [144]. In humans, ghrelin peaks before customary ingestive events [145,146] and it is inferred that this promotes feeding. However, evidence that ghrelin shortens the inter-ingestive interval in humans is lacking. In contrast to this purported role, infusion of ghrelin has led to increased energy intake at a buffet meal in lean and obese humans [147] and greater energy intake in malnourished dialysis [148] and cancer [149] patients. Thus, it increased portion size. Overall, there are compelling data that administration of selected “satiety hormones” leads to reduced energy intake, and administration of ghrelin can increase energy consumption. The evidence is less clear that endogenous secretion of these peptides modulates appetite and intake in free-living individuals. The perspective that these peptides are satiation signals fails to account for effects on ingestive frequency and likely hampers characterization of their role in ingestive behavior and


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energy balance. However, the reciprocity between the orexigenic and anorectic signals they evoke is clearly not sufficiently precise to prevent weight gain by the majority of the population. This may reflect, 1) a lack of a true regulatory system [7], 2) insensitivity and limited power of these signaling molecules under customary ingestive conditions (but perhaps strong influences under more extreme conditions [9]; or 3) domination of biological controls by environmental factors [150]. 2.3. Environmental modulation of portion There are multiple environmental drivers of a direct association between portion size and energy intake. One is the ethical concern about wasting food [151,152]. Second, the majority of people indicate that they intend to finish all that is on their plate or in a package at the expense of reaching an optimal level of fullness [22,153]. A third influence is cultural norms that may define customary or desirable portion sizes [154–156]. As this increases, there is greater license, and possibly peer-pressure, to ingest more per ingestive occasion. A fourth contributor may be an increase in distracted eating [157]. The American Time Use Survey indicates that there has been a sharp increase in secondary eating and drinking which is defined as eating or drinking when engaged in some other primary activity such as driving a car or watching television (http://www.ers.usda.gov/Data/ATUS/Data). This may contribute as attention to visual cues is inversely related to energy intake [158]. Fifth, nutrition information and perception can promote intake of increased portion sizes. Increasing food volume [33,159], viscosity [160], labeling an item as low energy [161] or high nutritional value [162], serving food in large containers [163] or covertly increasing portion size by reducing cues to its consumption [163] are examples of messaging that can result in greater energy intake. 2.4. Environmental modulation of ingestive frequency A simple depletion–repletion model does not adequately account for human ingestive behavior. The overnight fast is generally the longest interval between ingestive events when satiety signals should be weak and hunger strong, yet hunger is not highest upon waking [62,164]. Constraints of daily living can determine the feasibility of initiating ingestive events; religious or health practices that entail food restriction can alter the timing and number of ingestive events, and the widespread availability of food and beverages coupled with increased social acceptability for eating or drinking in non-traditional venues (e.g., automobiles, offices) can increase ingestive frequency. While biological cues can simply be overridden by environmental inputs, an interaction is also documented. Analysis of feeding in humans suggests that growth of hunger is strikingly constant [165], suggestive of some control mechanism(s). A food entrainable oscillator that is set by lifestyle has been proposed [166]. Animals, including humans, rapidly learn about the timing of regular eating patterns and demonstrate anticipatory behaviors and physiological processes such as insulin [167] or ghrelin [145] secretion, greater NPY concentration in the arcuate nucleus [168] or elevated metabolic rate [169] preceding customary eating occasions. Exposure to feeding cues can elicit similar responses [170]. Such a system may be consistent with reports of a positive association between ingestive frequency and BMI. With higher ingestive frequency, there are less marked oscillations of circulating nutrients and metabolites that may serve as signals to moderate appetite. For example, fluctuations of ghrelin related to changing insulin concentrations are blunted with frequent eating possibly leading to increased intake [171]. The mechanistic evidence outlined above indicates that there are both biological and environmental influences on the portion size of ingestive events and ingestive frequency of humans. Further, the two facets of ingestive behavior are reciprocally related, but clearly not precisely as the population's BMI has increased markedly over the past 35 years. This raises the question of what is a bigger and more tractable

contributor to weight gain? With limited resources, difficult decisions must be made about where, when and how to intervene. 3. Is portion size or ingestive frequency a bigger problem? The data on consumption trends for portion size and ingestive frequency are largely uncontested. Both have increased over the past 35 years [25]. However, the patterns are not consistent and this permits hypotheses about where the larger problem lies. Based upon data from four NHANES cycles, portion size increased by approximately 12% between 1977–78 and 2003–06. In contrast, ingestive frequency increased by about 29% over this time frame, in closer accord with total energy intake, which rose by approximately 32% [25]. The annualized contribution of portion size to total daily energy intake was 10% whereas it was more than double that, 22%, for ingestive frequency. Further, while portion size plateaued between 1994–98 and 2003–06, ingestive frequency and total energy intake continued to increase by about 14% and 11%, respectively. A stronger association between ingestive frequency and energy intake has also been reported based on CSFII data. Between 1977–78 and 1994–96, the energy intake per ingestive occurrence decreased by about 0.1% and 0.3% in males and females, respectively [172]. At the same time, ingestive frequency increased 16% and 15% in concert with total energy intake which increased 13% and 9% in males and females, respectively. In this latter analysis energy intake in self-reported breakfast, lunch and dinner increased by only 27 kcal in males and decreased by 17 kcal in females whereas each sex added about 0.6 ingestive occurrences during that time period. Snacks may be especially problematic for weight gain by multiple mechanisms. First, studies in rodents reveal that as the cost of eating increases portion size and the inter-ingestive interval increase [92]. Consistent with this observation, the increased emphasis on convenience, the low cost of food and its superabundance [74] has lowered the barriers to ingestion and there has been a corresponding reduction of the interval between ingestive events [20]. Second, while meal skipping is also prevalent, snacks generally increase the number of ingestive occurrences per day. Experimentally imposed increases in ingestive frequency lead to only partial dietary compensation ~55–65% resulting in higher total energy intake [173]. This can be problematic under free-living conditions because “non-meal” eating occurrences tend to be lower in energy and suppress appetite only transiently [174] so that by the time the next customary ingestive occasion occurs, there is little residual effect and, as a result, limited compensation [62,81,118,175–177]. This may be especially true for beverage-only eating occurrences [20,74,81,178]. Third, there is little effect of increased ingestive frequency on the thermogenic effect of feeding [72,179] while increased portion size is positively related to thermogenesis [180]. In a direct comparison, the thermogenic response to feeding is greater to a fixed energy load presented as a large portion compared to multiple smaller portions [181]. Thus, the net energy balance is greater with increased ingestive frequency. Fourth, frequent ingestive events reduce variations in insulin concentrations and, as a result, ghrelin concentrations. The lack of a normal pattern of hormone responses could blunt appetitive signaling and ingestive responses [171]. Fifth, the energy density of snacks is often higher than the balance of the diet. Indeed, between 1977–8 and 1994–6, the energy density of the US diet not including snacks did not change whereas the energy density of snacks increased by 26% [182]. Though it is not suggested that positive energy balance stems from only increased ingestive frequency, these observations indicate that it may be more problematic than the trends in portion size so a more important target for intervention. 4. Conclusion It is our proposition that positive energy balance stems more from high energy intake than low energy expenditure so to adequately address the problem of overweight/obesity, a better understanding of



ingestive behavior is required. This will entail better characterization of the drivers of ingestive frequency and portion size. More specifically, improved elucidation of the interaction between the two is required. The prevailing view is that biologically, portion size is the more important determinant of energy balance (e.g., [150]). However, we suggest that this reflects the current emphasis on gut signaling systems which are primarily viewed as regulators of satiation. This characterization may under-emphasize contributions of gut peptides to inter-ingestive intervals and fails to adequately integrate metabolic signals that largely target ingestive frequency. Behavioral data more strongly support an effect of ingestive frequency on positive energy balance. The magnitude of changes attributable to ingestive frequency is more consistent with increases in total energy intake than estimated effects of increased portion size. Additionally, the time course of ingestive frequency changes map better onto trends of body weight than the changes of portion size. Both grew in concert with BMI between the late 1970s and mid-1990s, but portion size then plateaued while ingestive frequency continued to rise with BMI over the next decade. Greater ingestive frequency has also been linked with rising BMI cross-culturally as the problem grows globally. The timing and size of ingestive events are both behavioral choices by consumers but mechanistic evidence indicates that compensatory dietary responses to greater ingestive frequency are weaker than to larger portion sizes rendering the former as more problematic for weight gain. Additionally, offsetting increases of energy expenditure are greater with increments of portion size than eating frequency. Thus, from a public health weight management perspective, greater attention to ingestive frequency may be warranted. 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