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Published in final edited form as: Physiol Behav. 2020 Feb 13;219:112830. doi: 10.1016/j.physbeh.2020.112830

Binge-like palatable food intake in rats reduces preproglucagon in the nucleus tractus solitarius

Ashmita Mukherjee a,*, Avery Hum b,*, Tyler J Gustafson c, Elizabeth G Mietlicki-Baase c,d
PMCID: PMC7108972  NIHMSID: NIHMS1560765  PMID: 32061682

Abstract

Binge eating involves eating larger than normal quantities of food within a discrete period of time. The neurohormonal controls governing binge-like palatable food intake are not well understood. Glucagon-like peptide-1 (GLP-1), a hormone produced peripherally in the intestine and centrally in the nucleus tractus solitarius (NTS), reduces food intake. Given that the NTS plays a critical role in integrating peripheral and central signals relevant for food intake, as well as the role of GLP-1 in motivated feeding, we tested the hypothesis that expression of the GLP-1 precursor preproglucagon (PPG) would be reduced in the NTS of rats with a history of binge-like palatable food intake. Adult male rats received access to fat for 1h shortly before lights off, either every day (Daily, D) or only 3d/week (Intermittent, INT). INT rats ate significantly more fat than did D rats in sessions where all rats had fat access. After ~8.5 weeks of diet maintenance, we measured plasma GLP-1 as well as NTS PPG and GLP-1 receptor expression. INT rats had significantly lower NTS PPG mRNA expression compared to D rats. However, plasma GLP-1 was significantly increased in the INT group versus D rats. No significant differences were observed in NTS GLP-1 receptor expression. We also measured plasma insulin levels, fasted blood glucose, and plasma corticosterone but no differences were detected between groups. These results support the hypothesis that binge-like eating reduces NTS GLP-1 expression, and furthermore, demonstrate divergent impacts of binge-like eating on peripheral (plasma) versus central GLP-1.

Keywords: binge eating, glucagon-like peptide-1, hindbrain

1. Introduction

Binge eating involves a loss of the control one normally experiences while consuming large portions of food. Often times, this loss of control over eating results in compulsive eating behavior, which is observed in several eating disorders such as bulimia nervosa, binge-purge type of anorexia nervosa, certain forms of obesity, and binge eating disorder, or BED [1, 2]. Apart from binge eating playing a role in several eating disorders, individuals who display binge eating behavior are also at a higher risk of developing health conditions such as obesity, hypertension and drug or alcohol use disorder [3–5]. There is neurobiological evidence of overlap between BED and substance use disorder [6–8]. In the United States, BED is one of the most common eating disorders, affecting almost 8% of American adults in their lifetime [9]. In fact, nearly 1 in 10 BED patients also suffer from alcohol use disorder [10]. Although it is well known that binge eating is associated with other eating disorders and dysregulated motivated behaviors, our understanding of the neurophysiological and neurohormonal changes that occur in relation to binge-like intake remains incomplete.

Currently, FDA-approved medications available for BED are limited; lisdexemfetamine, a psychostimulant used in treating ADHD, is now FDA-approved for the treatment of BED [11]. Since pharmacological treatment options for binge eating are limited, researchers have been examining other potential treatments that might suppress binge-like eating behavior. Medications that suppress appetite directly or that are associated with weight loss as a side effect have been examined [12], making it important to identify novel feeding related signals that could be targeted to reduce binge eating.

Feeding behavior is controlled by numerous integrated biological mechanisms that influence food intake. Glucagon-like peptide-1 (GLP-1) is a peptide hormone that plays an important role in feeding behavior by suppressing food intake [13]. GLP-1 is produced via cleavage of the precursor molecule preproglucagon (PPG) peripherally in a subset of intestinal enteroendocrine cells, as well as centrally in the nucleus of the solitary tract (NTS), a hindbrain structure critical for integration of information related to energy balance control [14, 15]. Central and peripheral GLP-1 release might play separable roles in controlling feeding behavior, although this is not yet fully understood [13, 16]. Non-nutrient-driven increases in peripheral GLP-1 have also been observed, which suggests that GLP-1 may play a role in meal anticipatory responses [17]. Furthermore, GLP-1 plays an important role in palatable food intake and motivation for food. Numerous studies demonstrate that central GLP-1 receptor (GLP-1R) activation in several different nuclei within the brain suppresses motivation to work for a palatable food [18–22] and GLP-1 receptor (GLP-1R) activation in certain brain areas selectively suppresses palatable food intake with no significant effect on chow intake [23].

Given the role of GLP-1 in the control of food intake and motivation for palatable food, some research has begun to investigate whether the GLP-1 system plays a role in eating disorders and in binge eating behavior [24–26]. One study showed that systemic administration of GLP-1 reduced hedonic sugar consumption in mice in a binge-eating paradigm of sucrose intake [27]. However, it remains unclear how the endogenous GLP-1 system may be changed as a result of binge eating and perhaps contribute to the development and/or maintenance of this behavior.

Here, we used a well-established model of binge-like eating in rodents to investigate how a history of binge-like palatable food intake impacts central GLP-1 expression and plasma GLP-1 levels. Specifically, rats were maintained on an intermittent palatable food access model developed by Corwin and colleagues [28–30] that produces binge-like intake in rats, and we tested the hypothesis that PPG expression in the NTS would be downregulated in rats with a history of binge-like palatable food intake (i.e., those with intermittent access to palatable food) compared to rats without such history (i.e., those with daily access to palatable food). We also investigated plasma levels of GLP-1, insulin, and corticosterone, as well as fasted blood glucose, in rats under these conditions.

2. Materials and Methods

2.1. Animals

Sixteen adult male Sprague Dawley rats (Charles River Laboratories) were used in this study. The rats were single housed in hanging wire cages in a temperature and humidity controlled environment, with ad libitum access to chow (Teklad 2018, Envigo) and water except where noted. A 12h:12h light cycle was used (lights on at 12:00AM, lights off at 12:00PM). All experimental procedures received approval from the University at Buffalo Institutional Animal Care and Use Committee.

2.2. Experimental design

After rats habituated to the animal facility, baseline measurements of feeding and body weight were collected according to methods previously described in the literature [31]. Assignments to daily (D) vs intermittent (INT) conditions were based on matching groups by: average chow intake for three baseline days over the one week period, fat intake overnight, and final body weight of the baseline period [31]. One rat was excluded from further analysis because it did not sample fat during the overnight access period. The baseline data for all rats included in the study are shown in Figure 1A–C (p>0.05 for 3-day average chow intake, overnight fat intake, and final baseline body weight). The remaining rats were divided into two groups matched for all baseline measurements (all p>0.05). One group was assigned to receive daily (D; n=7) 1 hour access to fat (vegetable shortening; Crisco®, J.M Smucker Company) and the other group was assigned to receive intermittent (INT; n=8) fat access, e.g., 1 hour access to fat only for 3 days a week (Mondays, Wednesdays, and Fridays). Fat was provided in a small glass jar clipped into the cage, and the access period began approximately 1.5h before lights off, consistent with methods previously described in the literature [31]. On days when fat was available to all rats, fat and chow intake were both measured. Food spillage was accounted for in all intake measurements. Body weights were also collected daily.

Figure 1: Baseline measurements and overview of binge experiment timeline.

Figure 1:

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Three-day average chow intake from first three days of baseline week (A), average overnight fat intake from baseline fat access (B), and final body weight from baseline week (C). A timeline of the experiment is shown in (D). Data were analyzed via two-tailed t-test and are shown as mean ± SEM (n=7 for D, n=8 for INT).

After ~8.5 weeks of D or INT maintenance [25 “binge sessions”, e.g. the hour of fat access on days in which all rats received fat (Mondays, Wednesdays, and Fridays)], rats were fasted overnight and sacrificed ~1–2h prior to the time of day that the fat access would have been provided. Each rat was deeply anesthetized via intramuscular injection of a cocktail containing ketamine (90mg/kg), acepromazine (0.64mg/kg), and xylazine (2.7mg/kg), and then decapitated. Brains were rapidly removed and flash frozen in isopentane, and stored at −80°C until sectioning. After decapitation, a small trunk blood sample was taken to measure blood glucose concentrations using a standard glucometer (OneTouch®). Remaining trunk blood was collected in EDTA-containing blood collection tubes on wet ice, then spun in a refrigerated centrifuge to separate plasma. The plasma samples were collected and stored at −80°C until further processing. A timeline for the entire experiment is shown in Figure 1D.

2.3. NTS sample collection and qPCR

Using a cryostat (Bright Ultrapro 5000), bilateral ~1mm3 medial NTS-enriched tissue punches were collected from each rat at the level of the area postrema, as previously described [32–34]. Quantitative real-time PCR (qPCR) was performed to measure central PPG and GLP-1 receptor expression in the NTS. Studies have shown that decreased NTS PPG mRNA expression is associated with reduced GLP-1 / GLP-1 fibers in afferent targets [35, 36] suggesting that changes in PPG expression are related to changes in central GLP-1.

Total RNA was isolated using TRIzol (Life Technologies) and the RNeasy Mini Kit (Qiagen). cDNA was synthesized using the iScript cDNA Synthesis Kit (Bio-Rad) and was amplified using the iTaq Universal SYBR Green Supermix (Bio-Rad) and analyzed with the CFX 96 Connect RT-PCR (Bio-Rad). The primer sequences are as follows: PPG sense, 5’-ACCGCCCTGAGATTACTTTTCTG-3’, antisense, 5’-AGTTCTCTTTCCAGGTTCACCAC-3’; GLP-1R sense, 5’-CCGGGTCATCTGCATCGT-3’, antisense, 5’ AGTCTGCATTTGATGTCGGTCTT-3’; GAPDH sense, 5’-AACGACC CCTTCATTGAC-3’, antisense, 5’-TCCACGACATACTCAGCAC-3’; selected from the literature [37]. Due to technical errors in tissue processing, some samples were excluded from the analysis resulting in final n=5–8/group. The comparative threshold cycle method [38] was used to determine relative mRNA expression of PPG and of GLP-1R, with GAPDH serving as the control.

2.4. Plasma sample processing

Plasma samples were thawed on wet ice and analyzed via ELISA for total GLP-1 (EMD Millipore), plasma insulin (EMD Millipore), and plasma corticosterone (Crystal Chem). In the plasma insulin ELISA, two samples were excluded due to high variability between duplicate wells (final n=7 for daily and n=6 for intermittent). For the plasma GLP-1 ELISA, three samples were excluded due to high variability and threshold errors, resulting in 12 samples (n=6 per group).

2.5. Data and statistical analyses

All data are represented as mean ± SEM. Binge session intake and body weight data were analyzed via mixed design ANOVA (TIBCO Statistica 13.3), accounting for the within-subject factor of time and the between-subject factor of assigned diet condition. Statistically significant effects in an overall ANOVA were probed using Student-Newman-Keuls posthoc analyses. In 2 instances of technical errors in food intake measurements, the values were calculated by taking the average of the measurements from the binge session immediately preceding and binge session immediately following the measurement error. Other data were analyzed via two-tailed T-test (Microsoft Excel, 2016). Hormone concentrations from ELISA were calculated based on manufacturer’s instructions. For all statistical analyses, a p-value of p<0.05 was considered statistically significant.

3. Results

3.1. Intermittent access to palatable food promotes binge-like food intake without changes in body weight

To test the hypothesis that NTS GLP-1 is downregulated in rats with a history of binge-like palatable food intake, it first needed to be established that rats were engaging in binge-like eating. Therefore, rats were given access to palatable food for 1h either every day of the week (Daily; D) or only 3 days/week (Intermittent; INT) for approximately 8.5 weeks of D or INT maintenance (25 “binge sessions”, e.g. days when all rats had fat access). Previous studies have shown that limiting access to palatable food can produce binge-like eating behavior in rodents [28–30]. Consistent with these findings, the rats that were given INT access to fat (vegetable shortening, which contains fat sources including soybean oil and fully hydrogenated palm oil) exhibited a binge-like pattern of intake, as they consumed more fat than did the D rats during the one-hour “binge session” periods (Figure 2A). Statistical analyses revealed a significant main effect of diet (F1,13=5.58, p<0.05) as well as a significant time x diet interaction (F24,312=2.28, p<0.05) but posthoc analyses revealed no significant differences between D and INT on any specific binge session (all p>0.05). The increased intake of fat in INT rats compared to that of D rats is consistent with previously published findings using an intermittent palatable food access model [39]. Chow intake was also measured during the 1h fat access period; however, there were no significant differences between the two groups in their one-hour chow intake whilst fat was available (Figure 2B; main effect of diet, F1,13=0.06, p>0.05; time x diet interaction, F24,312=1.21; p>0.05). Although INT rats ate significantly larger amounts of fat during the 1h access period, their daily total energy intake from all food sources did not significantly differ from that of D rats (Figure 2C; main effect of diet, F1,13=0.38, p>0.05; time x diet interaction, F24,312=2.30, p<0.05; posthoc analyses comparing D versus INT showed no significant differences on any given binge session, all p>0.05). Finally, there were no significant differences observed in body weight between the D and INT groups (Figure 2D; main effect of diet, F1,13=0.38, p>0.05; time x diet interaction, F24,312=1.67, p<0.05; posthoc analyses comparing D versus INT showed no significant differences on any given binge session, all p>0.05).

Figure 2: Intermittent access to palatable food produces binge-like behavior in rodents.

Figure 2:

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(A) Fat intake during the 1 hour in which it was made available during “binge sessions”, i.e., days on which all rats had fat available. INT rats consumed more fat than did D rats. Chow intake during the 1 hour binge sessions (B), daily total energy intake from chow and fat on binge session days (C), and body weight on binge session days (D) were not different between groups. Data are shown as mean ± SEM (n=7 for D, n=8 for INT; *, main effect of diet condition, p<0.05). Data were analyzed via mixed design ANOVA, accounting for the within-subject factor of time and the between-subject factor of assigned diet condition. Statistically significant effects in an overall ANOVA were probed using Student-Newman-Keuls posthoc analyses. Key in panel (A) applies to all panels.

3.2. Intermittent access to palatable food suppresses NTS PPG expression

After approximately 8.5 weeks of D or INT maintenance (25 “binge sessions”), rats were sacrificed to assess central and peripheral GLP-1 expression. In the brain, the GLP-1 precursor PPG as well as levels of the GLP-1 receptor (GLP-1R) were assessed in the NTS via qPCR. INT rats had significantly lower PPG mRNA expression in the NTS compared to the daily group (Figure 3A; p<0.05). NTS GLP-1 receptor expression was not significantly different between the INT and D groups (Figure 3B; p>0.05), suggesting that the changes evaluated in the NTS that occurred were limited to PPG rather than GLP-1 receptor expression.

Figure 3: Binge-like palatable food intake reduces NTS preproglucagon expression.

Figure 3:

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Rats with a history of D or INT fat intake were sacrificed after ~8.5 weeks of diet maintenance. Relative mRNA expression of PPG in the NTS was reduced in INT rats compared to D rats (A), with no differences between groups in relative expression of GLP-1R mRNA in the NTS (B). Data were analyzed via two-tailed t-test and are shown as mean ± SEM (n=5–8/group; *, p<0.05).

3.3. Rats with intermittent access to palatable food show an increase in plasma GLP-1

The effects of central and peripheral GLP-1 may be dissociable [13] so we examined the GLP-1 levels in the periphery by examining plasma levels of GLP-1. Plasma GLP-1 concentration was significantly higher in INT rats compared to D rats (Figure 4A; p<0.05). There has been evidence suggesting an increase in plasma GLP-1 can occur as a meal anticipatory response [17, 40]. Our data align with this finding as the rats were sacrificed around the same time of day they would have received their one-hour fat access. GLP-1 augments insulin release from the pancreas [14], thereby playing an important role in glycemic control. Given this role of GLP-1, we also assessed whether changes in blood glucose levels or plasma insulin occurred in INT versus D rats. No significant differences were observed in plasma insulin levels (Figure 4B; p>0.05) or fasted blood glucose (Figure 4C; p>0.05) between the two groups.

Figure 4: Plasma GLP-1 levels are increased in INT versus D rats.

Figure 4:

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Blood samples were collected from all rats at time of sacrifice. Plasma GLP-1 concentrations were increased in INT rats (A). There were no differences between INT and D rats for plasma insulin concentration (B), fasted blood glucose (C), or plasma corticosterone concentration (D). Data were analyzed via two-tailed t-test and are shown as mean ± SEM (n=6–8/group; *, p<0.05).

Research has shown that GLP-1 can increase corticosterone levels by triggering the hypothalamic-pituitary-adrenal axis [41–43]. As both human and non-human animal studies show that binge-like eating can be associated with stress [44, 45], we examined plasma corticosterone concentration in INT and D rats. No significant difference was detected in plasma corticosterone levels between D and INT groups (Figure 4D; p>0.05).

4. Discussion

Previous literature has implicated GLP-1 in influencing factors that may be related to binge eating such as motivation, reward, and feeding, yet whether GLP-1 plays a role in binge eating is not well understood. In the current study, we tested the hypothesis that NTS GLP-1 expression would be decreased in rats with a history of binge-like behavior. Our results indicated that INT rats, which have a history of binge-like palatable food intake compared to the D rats, had reduced NTS PPG mRNA levels but increased plasma GLP-1. These changes occurred independent of changes in body weight, NTS GLP-1R expression, plasma insulin, blood glucose, and plasma corticosterone levels. These data provide evidence that the GLP-1 system changes after engaging in binge-like eating over several weeks, and furthermore demonstrate an intriguing dissociation of the effects on central versus peripheral GLP-1.

Our data show that INT rats ate more fat during “binge sessions” than rats given D access to fat. These results are consistent with those previously shown by Corwin and colleagues [28, 46], where limited access to energy-dense, palatable foods induces overconsumption when the food is available, e.g., binge-like eating. No significant differences were observed in overall energy intake or body weight on “binge session” days between the two groups of rats. This observation supports the notion that binge-like eating behavior itself is not necessarily linked to weight gain and consequently obesity [9, 47].

Previous studies have shown that GLP-1R stimulation in several areas of the brain reduced food intake and body weight [48–50]. Holt et al. describe the role of PPG neurons to be most important when large quantities of food are consumed [49]. The current study shows that INT rats had significantly lower levels of PPG mRNA expression in the NTS than D rats prior to palatable food access. Rats that regularly engage in binge-like eating might reasonably be expected to have lower levels of relevant satiation signals, including GLP-1. It is not certain whether the levels of PPG mRNA expression increased after binge-like activity consistent with the effects described by Holt et al. [49]. However, a previous study has suggested that some alterations in central gene expression are normalized after bingeing in rodents [51]. Specifically, pre-binge alterations in mRNA levels of certain genes related to GABAergic and dopaminergic neurotransmission were normalized after binge-like intake of a palatable food [51]. As GLP-1 normally plays a role in suppressing food intake, it is possible that engaging in binge-like intake increases hindbrain GLP-1 to restrain further food intake and eventually stop the binge-like eating episode. This could be due several factors related to the food itself, such as its nutritive value or the volume ingested [52–54]. It will be important in future studies to determine whether NTS PPG mRNA levels are normalized post-binge, as this would be consistent with the ability of GLP-1 to suppress further intake of palatable food [21, 23, 41].

Interestingly, our data show that in contrast to the reduction in NTS PPG, plasma GLP-1 concentrations were significantly increased in INT rats. As rats were sacrificed shortly prior to the time of the usual fat access period, it is possible that this increase in plasma GLP-1 concentration may be an anticipatory response prior to palatable food access. A previous study provided evidence for anticipatory release of GLP-1 before a scheduled meal [17], with a significant surge in peripheral GLP-1 prior to food introduction. GLP-1 also can increase gastric volume and compliance to increase the capacity for food [55, 56]. Therefore, this pre-prandial GLP-1 surge may act to facilitate intake when anticipating a large meal. This increase in GLP-1 was also independent of changes in blood glucose and insulin [17], which aligns well with our findings. It should be noted that Vahl and colleagues observed the rise in peripheral GLP-1 about 1 hour prior to the start of scheduled daily meals but this rise had returned to baseline by the time of meal onset. Due to the difference in the meal-feeding schedules and types of food available, it is difficult to make a direct comparison between Vahl et al. [17] and our present data. However, our rats were sacrificed approximately 1 hour prior to their scheduled food access, which follows closely with the timing of the Vahl et al. study [17] and suggests that the increase in plasma GLP-1 prior to scheduled fat access in the INT rats here could reflect a similar anticipatory mechanism. It is important to note that our study evaluated plasma GLP-1 and NTS PPG only at one timepoint, prior to the usual fat access period. It is currently unknown whether or how plasma GLP-1 and NTS PPG may change in D vs INT rats after access to the palatable food. Thus, it is also possible that the changes we have observed reflect tonic changes to peripheral and central GLP-1. Future studies will need to examine how GLP-1 changes at various times, prior to the binge session but also during and after the session, to fully understand the timecourse of the changes in the GLP-1 system in the INT versus D rats.

GLP-1-producing neurons in the NTS are activated by particularly large meals [52, 53]. Rather than examining activation of NTS PPG neurons by binge-like intake, we used qPCR to assess expression of PPG within the NTS. Our results suggest the intriguing notion that, even if these PPG neurons are activated by ingestion of a large amount of food such as that which presumably occurs in a binge session in INT rats, the amount of GLP-1 available for release may be reduced. Importantly, however, GLP-1R expression in the NTS was not different between D and INT rats in our study. Previous work by others has shown that GLP-1R expression may be influenced by intermittent caloric restriction [57], consistent with the idea that different schedules of food access may impact GLP-1R and GLP-1. It will also be worth examining in future studies whether GLP-1R activation in key feeding-relevant nuclei is altered in rats with a history of binge-like intake, particularly in reward-related areas of the brain such as the mesolimbic system, which is thought to be an important neural substrate underlying binge eating [58].

Another interesting result that we observed is the lack of significant difference in insulin levels between the two groups. Previous studies have demonstrated that peripheral insulin increases just before a meal is introduced [17]. Although in our study there were differences in 1h fat intake between D and INT rats, we did not detect a difference in plasma insulin between groups. This suggests that a history of binge-like intake does not alter plasma insulin levels prior to a scheduled binge session, although the lack of difference could be related to the timing of the sacrifice relative to normal time of food availability [17]. It is also possible that meal-stimulated insulin levels are different between groups.

Stress can also play a role in affecting changes in GLP-1 [42, 59] which in turn may subsequently have an effect on feeding behavior. Increased peripheral corticosterone can activate NTS GLP-1-producing neurons [43] and exposure to stressors can reduce PPG expression in the NTS [35]. It has also been demonstrated that central GLP-1R activation increases plasma corticosterone levels [60, 61]. To rule out the possibility that a stress-related mechanism may have potentially played a role in our results, we compared plasma corticosterone levels in INT and D rats but found no differences between groups. Thus, stress is unlikely to explain the differences in NTS PPG expression between groups.

The role of GLP-1 in reward and motivated behaviors other than feeding has been increasingly studied in recent years [41, 62, 63]. In particular, a growing body of literature provides evidence for a role of GLP-1 signaling in drug taking and seeking [63–66]. There is a high comorbidity between disordered eating and other dysregulated motivated behaviors, such as drug use [67–69]. A previous rodent study found that binge-like eating of fat enhances cocaine seeking and administration [70]. It is clear that there is shared neural circuitry underlying food and drug intake [71]; to speculate, the GLP-1 system may be a point of convergence between these behaviors. This is an important area of research that deserves further investigation. These and other findings highlight the need to identify neural and/or neuroendocrine mechanisms that may link disordered patterns of intake such as binge eating with the increased risk for addiction [4, 8].

Strengths of the current studies include novel investigation of how the GLP-1 system is impacted by a history of binge-like palatable food intake. Further, both peripheral and central GLP-1 levels are examined, which is particularly important as these may diverge [49]. We also ruled out the contribution of other factors such as blood glucose levels, insulin, and corticosterone to the changes observed in GLP-1. The studies thus provide key evidence that binge-like eating changes GLP-1 expression centrally and peripherally. The research, however, is subject to several limitations. First, this study examined the association between GLP-1 and binge-like palatable food intake, and further studies must investigate whether GLP-1 also plays a causal role in binge-like feeding. We measured physiological changes in variables of interest at only one timepoint, and future studies will need to evaluate time course of changes in GLP-1, both in terms of the development of these changes relative to exposure to binge-like eating, as well as whether changes occur relative to a binge session, similar to other neurobiological changes observed in previous work [30, 51]. Additionally, it is imperative to note that we did not include a group that did not receive fat access. In future experiments, it will be important to include a control group that does not receive any fat access to provide a deeper understanding of how central and peripheral GLP-1 levels are impacted by consumption of palatable food. Finally, binge eating disorder is more prevalent in women than men [9]; hence, it will be important to examine the possible association of GLP-1 and binge-like feeding in female rats. Despite these limitations, our studies nevertheless provide foundational evidence that GLP-1 is associated with binge-like feeding. Furthermore, these results lay the groundwork to examine sex differences in these responses and to perform behavioral pharmacology experiments with agonists and antagonists of the GLP-1R to gain a better understanding of how and where receptor activation could impact binge-like feeding.

5. Conclusions

In summary, our results indicate that rats that engaged in binge-like intake of palatable foods over several weeks had decreased NTS PPG mRNA, suggesting a downregulation of central GLP-1 signaling. Further, our data demonstrate that binge-like feeding differentially impacts peripheral and central GLP-1 systems, as INT rats had increased total plasma GLP-1 compared to levels in D rats. These data suggest divergent roles of peripheral and central GLP-1 in binge-like intake of palatable foods, and to our knowledge, represent the first data to demonstrate a dissociation of central and peripheral GLP-1 responses in a model of binge eating. These findings further contribute to our understanding of how binge-like food intake may alter key neurohormonal systems relevant to energy balance control. Gaining a clearer understanding of the role that GLP-1 may play in mediating binge-like behavior may shed light onto new strategies to reduce binge eating.

Supplementary Material

1

Highlights.

  • Binge-like feeding reduces preproglucagon in nucleus tractus solitarius (NTS).

  • Binge-like feeding increases plasma glucagon-like peptide-1 (GLP-1).

  • Binge-like intake differentially impacts NTS GLP-1 expression vs plasma GLP-1.

  • Blood glucose, insulin, and corticosterone were not changed by binge-like feeding.

Acknowledgements

The authors thank Shtakshe Chatrath, Katlyn Kelly, Houda Nashawi, Madeline Norton, and Yibo Xie for valuable technical assistance. This work was supported by a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation; the National Institutes of Health (DK114211); and start-up funds from the University at Buffalo (EGM-B).

Footnotes

Declaration of Interest: The authors have nothing to disclose.

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References

  • [1].Moore CF, Sabino V, Koob GF, Cottone P Neuroscience of Compulsive Eating Behavior. Front Neurosci. 2017,11:469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Burton AL, Abbott MJ Processes and pathways to binge eating: development of an integrated cognitive and behavioural model of binge eating. J Eat Disord. 2019,7:18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Grilo CM, White MA, Masheb RM DSM-IV psychiatric disorder comorbidity and its correlates in binge eating disorder. Int J Eat Disord. 2009,42:228–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Ross HE, Ivis F Binge eating and substance use among male and female adolescents. Int J Eat Disord. 1999,26:245–60. [DOI] [PubMed] [Google Scholar]
  • [5].Olguin P, Fuentes M, Gabler G, Guerdjikova AI, Keck PE Jr., McElroy SL Medical comorbidity of binge eating disorder: response. Eat Weight Disord. 2017,22:725–6. [DOI] [PubMed] [Google Scholar]
  • [6].Smith DG, Robbins TW The neurobiological underpinnings of obesity and binge eating: a rationale for adopting the food addiction model. Biol Psychiatry. 2013,73:804–10. [DOI] [PubMed] [Google Scholar]
  • [7].Schreiber LR, Odlaug BL, Grant JE The overlap between binge eating disorder and substance use disorders: Diagnosis and neurobiology. J Behav Addict. 2013,2:191–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Schulte EM, Grilo CM, Gearhardt AN Shared and unique mechanisms underlying binge eating disorder and addictive disorders. Clin Psychol Rev. 2016,44:125–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Hudson JI, Hiripi E, Pope HG Jr., Kessler RC The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry. 2007,61:348–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Ulfvebrand S, Birgegard A, Norring C, Hogdahl L, von Hausswolff-Juhlin Y Psychiatric comorbidity in women and men with eating disorders results from a large clinical database. Psychiatry Res. 2015,230:294–9. [DOI] [PubMed] [Google Scholar]
  • [11].Hudson JI, McElroy SL, Ferreira-Cornwell MC, Radewonuk J, Gasior M Efficacy of Lisdexamfetamine in Adults With Moderate to Severe Binge-Eating Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2017,74:903–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Bulik CM, Brownley KA, Shapiro JR Diagnosis and management of binge eating disorder. World Psychiatry. 2007,6:142–8. [PMC free article] [PubMed] [Google Scholar]
  • [13].Dailey MJ, Moran TH Glucagon-like peptide 1 and appetite. Trends Endocrinol Metab. 2013,24:85–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Holst JJ The physiology of glucagon-like peptide 1. Physiol Rev. 2007,87:1409–39. [DOI] [PubMed] [Google Scholar]
  • [15].Grill HJ, Hayes MR Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab. 2012,16:296–309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Turton MD, O’Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996,379:69–72. [DOI] [PubMed] [Google Scholar]
  • [17].Vahl TP, Drazen DL, Seeley RJ, D’Alessio DA, Woods SC Meal-anticipatory glucagon-like peptide-1 secretion in rats. Endocrinology. 2010,151:569–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Terrill SJ, Holt MK, Maske CB, Abrams N, Reimann F, Trapp S, et al. Endogenous GLP-1 in lateral septum promotes satiety and suppresses motivation for food in mice. Physiol Behav. 2019,206:191–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Lopez-Ferreras L, Richard JE, Noble EE, Eerola K, Anderberg RH, Olandersson K, et al. Lateral hypothalamic GLP-1 receptors are critical for the control of food reinforcement, ingestive behavior and body weight. Mol Psychiatry. 2018,23:1157–68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Richard JE, Anderberg RH, Goteson A, Gribble FM, Reimann F, Skibicka KP Activation of the GLP-1 receptors in the nucleus of the solitary tract reduces food reward behavior and targets the mesolimbic system. PLoS One. 2015,10:e0119034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Dickson SL, Shirazi RH, Hansson C, Bergquist F, Nissbrandt H, Skibicka KP The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors. J Neurosci. 2012,32:4812–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Alhadeff AL, Baird JP, Swick JC, Hayes MR, Grill HJ Glucagon-like Peptide-1 receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake and motivation to feed. Neuropsychopharmacology. 2014,39:2233–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Alhadeff AL, Rupprecht LE, Hayes MR GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake. Endocrinology. 2012,153:647–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Naessen S, Carlstrom K, Holst JJ, Hellstrom PM, Hirschberg AL Women with bulimia nervosa exhibit attenuated secretion of glucagon-like peptide 1, pancreatic polypeptide, and insulin in response to a meal. Am J Clin Nutr. 2011,94:967–72. [DOI] [PubMed] [Google Scholar]
  • [25].Brambilla F, Monteleone P, Maj M Glucagon-like peptide-1 secretion in bulimia nervosa. Psychiatry Res. 2009,169:82–5. [DOI] [PubMed] [Google Scholar]
  • [26].Tomasik PJ, Sztefko K, Malek A GLP-1 as a satiety factor in children with eating disorders. Horm Metab Res. 2002,34:77–80. [DOI] [PubMed] [Google Scholar]
  • [27].Yamaguchi E, Yasoshima Y, Shimura T Systemic administration of anorexic gut peptide hormones impairs hedonic-driven sucrose consumption in mice. Physiol Behav. 2017,171:158–64. [DOI] [PubMed] [Google Scholar]
  • [28].Corwin RL, Babbs RK Rodent models of binge eating: are they models of addiction? Ilar j. 2012,53:23–34. [DOI] [PubMed] [Google Scholar]
  • [29].Dimitriou SG, Rice HB, Corwin RL Effects of limited access to a fat option on food intake and body composition in female rats. Int J Eat Disord. 2000,28:436–45. [DOI] [PubMed] [Google Scholar]
  • [30].Corwin RL, Wojnicki FH, Fisher JO, Dimitriou SG, Rice HB, Young MA Limited access to a dietary fat option affects ingestive behavior but not body composition in male rats. Physiol Behav. 1998,65:545–53. [DOI] [PubMed] [Google Scholar]
  • [31].Corwin RL, Wojnicki FH Binge eating in rats with limited access to vegetable shortening. Curr Protoc Neurosci. 2006,Chapter 9:Unit9 23B. [DOI] [PubMed] [Google Scholar]
  • [32].Rupprecht LE, Mietlicki-Baase EG, Zimmer DJ, McGrath LE, Olivos DR, Hayes MR Hindbrain GLP-1 receptor-mediated suppression of food intake requires a PI3K-dependent decrease in phosphorylation of membrane-bound Akt. Am J Physiol Endocrinol Metab. 2013,305:E751–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Liberini CG, Koch-Laskowski K, Shaulson E, McGrath LE, Lipsky RK, Lhamo R, et al. Combined Amylin/GLP-1 pharmacotherapy to promote and sustain long-lasting weight loss. Sci Rep. 2019,9:8447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Alhadeff AL, Mergler BD, Zimmer DJ, Turner CA, Reiner DJ, Schmidt HD, et al. Endogenous Glucagon-like Peptide-1 Receptor Signaling in the Nucleus Tractus Solitarius is Required for Food Intake Control. Neuropsychopharmacology. 2017,42:1471–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Zhang R, Packard BA, Tauchi M, D’Alessio DA, Herman JP Glucocorticoid regulation of preproglucagon transcription and RNA stability during stress. Proc Natl Acad Sci U S A. 2009,106:5913–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Barrera JG, Jones KR, Herman JP, D’Alessio DA, Woods SC, Seeley RJ Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function. J Neurosci. 2011,31:3904–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [37].McKay NJ, Galante DL, Daniels D Endogenous glucagon-like peptide-1 reduces drinking behavior and is differentially engaged by water and food intakes in rats. J Neurosci. 2014,34:16417–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [38].Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med. 2006,12:917–24. [DOI] [PubMed] [Google Scholar]
  • [39].Sirohi S, Van Cleef A, Davis JF Intermittent access to a nutritionally complete high-fat diet attenuates alcohol drinking in rats. Pharmacol Biochem Behav. 2017,153:105–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Williams DL Expecting to eat: glucagon-like peptide-1 and the anticipation of meals. Endocrinology. 2010,151:445–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Hayes MR, Schmidt HD GLP-1 influences food and drug reward. Curr Opin Behav Sci. 2016,9:66–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Gil-Lozano M, Perez-Tilve D, Alvarez-Crespo M, Martis A, Fernandez AM, Catalina PA, et al. GLP-1(7–36)-amide and Exendin-4 stimulate the HPA axis in rodents and humans. Endocrinology. 2010,151:2629–40. [DOI] [PubMed] [Google Scholar]
  • [43].Schmidt HD, Mietlicki-Baase EG, Ige KY, Maurer JJ, Reiner DJ, Zimmer DJ, et al. Glucagon-Like Peptide-1 Receptor Activation in the Ventral Tegmental Area Decreases the Reinforcing Efficacy of Cocaine. Neuropsychopharmacology. 2016,41:1917–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [44].Hagan MM, Wauford PK, Chandler PC, Jarrett LA, Rybak RJ, Blackburn K A new animal model of binge eating: key synergistic role of past caloric restriction and stress. Physiol Behav. 2002,77:45–54. [DOI] [PubMed] [Google Scholar]
  • [45].Gluck ME Stress response and binge eating disorder. Appetite. 2006,46:26–30. [DOI] [PubMed] [Google Scholar]
  • [46].Kosheleff AR, Araki J, Tsan L, Chen G, Murphy NP, Maidment NT, et al. Junk Food Exposure Disrupts Selection of Food-Seeking Actions in Rats. Front Psychiatry. 2018,9:350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [47].Armentano Bittencourt S, Lucena-Santos P, Moraes J, Oliveira M Anxiety and depression symptoms in women with and without binge eating disorder enrolled in weight loss programs. Trends in Psychiatry and Psychotherapy. 2011,34:87–92. [DOI] [PubMed] [Google Scholar]
  • [48].Gaykema RP, Newmyer BA, Ottolini M, Raje V, Warthen DM, Lambeth PS, et al. Activation of murine pre-proglucagon-producing neurons reduces food intake and body weight. J Clin Invest. 2017,127:1031–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [49].Holt MK, Richards JE, Cook DR, Brierley DI, Williams DL, Reimann F, et al. Preproglucagon Neurons in the Nucleus of the Solitary Tract Are the Main Source of Brain GLP-1, Mediate Stress-Induced Hypophagia, and Limit Unusually Large Intakes of Food. Diabetes. 2019,68:21–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [50].Liu J, Conde K, Zhang P, Lilascharoen V, Xu Z, Lim BK, et al. Enhanced AMPA Receptor Trafficking Mediates the Anorexigenic Effect of Endogenous Glucagon-like Peptide-1 in the Paraventricular Hypothalamus. Neuron. 2017,96:897–909 e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Corwin RL, Wojnicki FH, Zimmer DJ, Babbs RK, McGrath LE, Olivos DR, et al. Binge-type eating disrupts dopaminergic and GABAergic signaling in the prefrontal cortex and ventral tegmental area. Obesity (Silver Spring). 2016,24:2118–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [52].Kreisler AD, Davis EA, Rinaman L Differential activation of chemically identified neurons in the caudal nucleus of the solitary tract in non-entrained rats after intake of satiating vs. non-satiating meals. Physiol Behav. 2014,136:47–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [53].Kreisler AD, Rinaman L Hindbrain glucagon-like peptide-1 neurons track intake volume and contribute to injection stress-induced hypophagia in meal-entrained rats. Am J Physiol Regul Integr Comp Physiol. 2016,310:R906–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [54].Bodnaruc AM, Prud’homme D, Blanchet R, Giroux I Nutritional modulation of endogenous glucagon-like peptide-1 secretion: a review. Nutr Metab (Lond). 2016,13:92. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [55].Schirra J, Wank U, Arnold R, Goke B, Katschinski M Effects of glucagon-like peptide-1(7–36)amide on motility and sensation of the proximal stomach in humans. Gut. 2002,50:341–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [56].Delgado-Aros S, Kim DY, Burton DD, Thomforde GM, Stephens D, Brinkmann BH, et al. Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans. Am J Physiol Gastrointest Liver Physiol. 2002,282:G424–31. [DOI] [PubMed] [Google Scholar]
  • [57].Bello NT, Yeh CY, James MH Reduced Sensory-Evoked Locus Coeruleus-Norepinephrine Neural Activity in Female Rats With a History of Dietary-Induced Binge Eating. Front Psychol. 2019,10:1966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [58].Naef L, Pitman KA, Borgland SL Mesolimbic dopamine and its neuromodulators in obesity and binge eating. CNS Spectr. 2015,20:574–83. [DOI] [PubMed] [Google Scholar]
  • [59].Ghosal S, Myers B, Herman JP Role of central glucagon-like peptide-1 in stress regulation. Physiol Behav. 2013,122:201–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [60].Kinzig KP, D’Alessio DA, Herman JP, Sakai RR, Vahl TP, Figueiredo HF, et al. CNS glucagon-like peptide-1 receptors mediate endocrine and anxiety responses to interoceptive and psychogenic stressors. J Neurosci. 2003,23:6163–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [61].Larsen PJ, Tang-Christensen M, Jessop DS Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat. Endocrinology. 1997,138:4445–55. [DOI] [PubMed] [Google Scholar]
  • [62].Skibicka KP The central GLP-1: implications for food and drug reward. Front Neurosci. 2013,7:181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [63].Sorensen G, Reddy IA, Weikop P, Graham DL, Stanwood GD, Wortwein G, et al. The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice. Physiol Behav. 2015,149:262–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [64].Hernandez NS, Ige KY, Mietlicki-Baase EG, Molina-Castro GC, Turner CA, Hayes MR, et al. Glucagon-like peptide-1 receptor activation in the ventral tegmental area attenuates cocaine seeking in rats. Neuropsychopharmacology. 2018,43:2000–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [65].Hernandez NS, O’Donovan B, Ortinski PI, Schmidt HD Activation of glucagon-like peptide-1 receptors in the nucleus accumbens attenuates cocaine seeking in rats. Addict Biol. 2019,24:170–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [66].Egecioglu E, Engel JA, Jerlhag E The glucagon-like peptide 1 analogue, exendin-4, attenuates the rewarding properties of psychostimulant drugs in mice. PLoS One. 2013,8:e69010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [67].Herzog DB, Franko DL, Dorer DJ, Keel PK, Jackson S, Manzo MP Drug abuse in women with eating disorders. Int J Eat Disord. 2006,39:364–8. [DOI] [PubMed] [Google Scholar]
  • [68].Franko DL, Dorer DJ, Keel PK, Jackson S, Manzo MP, Herzog DB Interactions between eating disorders and drug abuse. J Nerv Ment Dis. 2008,196:556–61. [DOI] [PubMed] [Google Scholar]
  • [69].Conason AH, Brunstein Klomek A, Sher L Recognizing alcohol and drug abuse in patients with eating disorders. QJM. 2006,99:335–9. [DOI] [PubMed] [Google Scholar]
  • [70].Puhl MD, Cason AM, Wojnicki FH, Corwin RL, Grigson PS A history of bingeing on fat enhances cocaine seeking and taking. Behav Neurosci. 2011,125:930–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [71].Kenny PJ, Voren G, Johnson PM Dopamine D2 receptors and striatopallidal transmission in addiction and obesity. Curr Opin Neurobiol. 2013,23:535–8. [DOI] [PMC free article] [PubMed] [Google Scholar]

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