Increased caloric intake after a high-fat preload: Relation to circulating triglycerides and orexigenic peptides
Introduction
There is extensive evidence showing overeating to occur in animals allowed to feed on a high-fat (HF) diet with greater than 40% fat compared to a low-fat (LF) diet with less than 20% fat. With diets available ad libitum, this increased consumption of a HF diet relative to a LF diet has been described under both chronic and acute conditions and in humans as well as rodents [1], [2], [3], [4], [5]. Rats maintained chronically on a HF diet, whether solid, liquid or semisolid, consume more daily calories then on a LF diet [5], [6], [7], [8], and this HF-induced overeating is observed even when a nutritionally complete food, standard lab chow, is present [7], [9]. With acute dietary manipulations, ad libitum consumption of a liquid or solid HF diet over a 1–3 h period produces a larger meal than with the LF diet, and this effect can be seen even when the animal itself infuses the liquid HF meal intragastrically [1], [10], [11], [12], [13]. This greater caloric intake occurs independently of the energy density of the meal, and it can be revealed in the form of a larger meal size as well as greater meal frequency [9], [12]. Similar results have been obtained in human studies, which show that dietary fat increases meal size as well as daily caloric intake [14].
Behavioral studies in rats and humans, under both chronic and acute conditions with ad libitum feeding, have focused on specific properties of a HF diet, most notably its greater palatability, greasy texture and energy density, as being important in the stimulation of eating behavior [2], [3], [15], [16], [17]. Dietary fat enhances the flavor of the other macronutrients in the mouth [18], and rats show a preference for a chow diet made greasy with a non-caloric mineral oil [17]. However, these properties alone do not increase food intake, as shown by the evidence that rats fail to overeat a greasy, mineral oil diet when given ad libitum [17]. Moreover, in studies that bypass the ingestion process, a HF solution continuously infused intragastrically or intravenously similarly increases caloric intake as compared to a chronically infused, equicaloric glucose solution [19], [20]. Whereas the higher energy density of a HF compared to LF diet may have some impact on caloric intake, the importance of this factor is also in question, since overeating can occur even when the diets are equal in caloric density [7], [12], [21], [22]. This evidence has led investigators to consider post-ingestive and post-absorptive factors in producing overeating, although information on such mechanisms has proven difficult to obtain using the ad libitum feeding paradigms. Free feeding on a chronic or acute HF diet increases body weight and body fat as well as daily caloric intake and meal size [2], [5], [6], [7], [12], [13], [16], [17]. Thus, any physiological and neurochemical changes observed in association with this greater caloric intake may be more a consequence of these factors than an indication of mechanisms causally related to the overeating on a fat-rich diet.
An acute feeding model, referred to as a “preload-to-test meal” paradigm, directly addresses this issue and therefore may help to elucidate mechanisms underlying the greater caloric intake associated with a HF relative to LF diet. This paradigm, which involves a HF or LF preload meal followed after a short interval by a test meal, is particularly useful in controlling for variables related to palatability, energy density and caloric intake, as well as body weight and adiposity. With these controls, one can investigate signals produced by a HF meal that, in addition to shortening the post-meal interval, promote overeating in a subsequent test meal [13], [22], [23]. In animal studies, there are reports with pure macronutrients that show a preload of corn oil to be less satiating than an equicaloric carbohydrate or protein preload and to be followed after 90 min by a larger test meal [22]. This HF-induced increase in caloric intake can be seen when the HF and LF preload diets are equal in energy density as well as caloric content [11], [24], [25], and it is evident across a range of preload volumes and intermeal intervals [11]. Moreover, it is observed when the preloads are equally palatable [11] or infused intragastrically [26], supporting the idea that palatability is not a key factor. In some [23], [27] but not all [22], [28] investigations in humans, food ingestion or gastric infusions demonstrate a similar pattern of reduced satiety and increased eating after a HF preload. Thus, the acute preload-to-test meal paradigm, with greater control of palatability, energy density and caloric intake compared to the ad libitum feeding paradigms, should be a useful tool in revealing mechanisms that precede and possibly contribute to the phenomenon of overeating in normal-weight animals.
The present report focused on this preload-to-test meal model. Building on the work of Warwick et al. [7], [9], [11], [12], [24], the first series of experiments set out to validate the increase in feeding effect in tests involving a variety of small preload diets (10–15 kcals), test meal diets, intermeal intervals and preload injections that bypass the ingestion process. With these tests standardizing a paradigm that consistently reveals greater food intake after a small HF preload, the next series of experiments examined in this preload-to-test meal model whether endocrine and neurochemical changes known to occur on a chronic HF diet can actually be detected prior to the increase in feeding. Studies to date with ad libitum consumption of a solid HF diet indicate that the overeating of fat attenuates responsiveness to the actions of gut peptides that normally inhibit feeding and slow gastric emptying [10], [29], [30] and to the satiety-producing effects of leptin and insulin [31], [32], [33], [34] and the melanocortin peptides [35]. It also increases circulating levels of triglycerides (TG) and stimulates the hypothalamic orexigenic peptides, galanin (GAL) and orexin (ORX), in close association with the rise in lipids [5], [36]. Since these peptides themselves stimulate a stronger feeding response on a HF compared to LF diet, they may provide the basis for a positive feedback loop whereby intake of a HF diet produces peptide changes that promote further consumption of this diet [33], [37], [38], [39]. Using the acute preload-to-test meal paradigm, the present experiments examined whether a single HF preload (10–15 kcals), relative to a LF preload equal in calories, energy density and palatability, is sufficient to produce an increase in TG levels and also to stimulate expression of these orexigenic peptides subsequent to the preload and prior to the increase in feeding. In the final experiment, these single HF preloads were given daily over a period of several days. This tested whether the acute changes in food intake, circulating TG and orexigenic peptide seen immediately after the HF preload can have long-term consequences, impacting perhaps on daily food consumption and body weight gain.
Section snippets
Subjects
Adult, male Sprague–Dawley rats (220–240 g) (Charles River Breeding Labs, Kingson, NY) were individually housed in plastic cages, in a fully accredited AAALAC facility (22 °C, with a 12:12-h light–dark cycle with lights off at 2 pm), according to institutionally approved protocols as specified in the NIH Guide to the Use and Care of Animals and also with the approval of the Rockefeller University Animal Care Committee. All animals were given 1 week to acclimate to the lab conditions before the
Experiment 1: food intake with liquid preload and diluted fat liquid test meal paradigm
This first experiment tested the effect of a liquid preload diet (50% fat, 0.67 kcal/ml) on intake of a subsequent liquid test meal. Cumulative measurements of the subsequent liquid meal, taken at 15, 30, 60, 90 and 120 min and averaged across the two test days, revealed significantly more food intake after the HF preload relative to the equicaloric LF preload (Fig. 1). This effect was strongest during the first 15 min of the test meal, when the HF preload was followed by a 45% increase (+
Behavioral model of HF-induced increase in food intake
The first 4 experiments of this report performed a variety of tests with modified versions of the preload-to-test meal paradigm originally described by Warwick and colleagues [9], [12], [24]. The purpose was to assess the robustness of the HF-induced feeding phenomenon under different conditions and then standardize a test paradigm in our lab that yielded a consistent effect and was easiest to administer. The different tests with a HF relative to LF preload revealed a greater feeding response
Acknowledgements
This research was supported by NIH grants MH 43422/DA 21518. We thank Mr. Joseph Shuluk for his help in the preparation of this manuscript.
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