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. 2016 May 15;310(10):R906-16.
doi: 10.1152/ajpregu.00243.2015. Epub 2016 Mar 2.

Hindbrain Glucagon-Like peptide-1 Neurons Track Intake Volume and Contribute to Injection Stress-Induced Hypophagia in Meal-Entrained Rats

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Free PMC article

Hindbrain Glucagon-Like peptide-1 Neurons Track Intake Volume and Contribute to Injection Stress-Induced Hypophagia in Meal-Entrained Rats

Alison D Kreisler et al. Am J Physiol Regul Integr Comp Physiol. .
Free PMC article

Abstract

Published research supports a role for central glucagon-like peptide 1 (GLP-1) signaling in suppressing food intake in rodent species. However, it is unclear whether GLP-1 neurons track food intake and contribute to satiety, and/or whether GLP-1 signaling contributes to stress-induced hypophagia. To examine whether GLP-1 neurons track intake volume, rats were trained to consume liquid diet (LD) for 1 h daily until baseline intake stabilized. On test day, schedule-fed rats consumed unrestricted or limited volumes of LD or unrestricted volumes of diluted (calorically matched to LD) or undiluted Ensure. Rats were perfused after the test meal, and brains processed for immunolocalization of cFos and GLP-1. The large majority of GLP-1 neurons expressed cFos in rats that consumed satiating volumes, regardless of diet type, with GLP-1 activation proportional to intake volume. Since GLP-1 signaling may limit intake only when such large proportions of GLP-1 neurons are activated, a second experiment examined the effect of central GLP-1 receptor (R) antagonism on 2 h intake in schedule-fed rats. Compared with baseline, intracerebroventricular vehicle (saline) suppressed Ensure intake by ∼11%. Conversely, intracerebroventricular injection of vehicle containing GLP-1R antagonist increased intake by ∼14% compared with baseline, partly due to larger second meals. We conclude that GLP-1 neural activation effectively tracks liquid diet intake, that intracerebroventricular injection suppresses intake, and that central GLP-1 signaling contributes to this hypophagic effect. GLP-1 signaling also may contribute to satiety after large volumes have been consumed, but this potential role is difficult to separate from a role in the hypophagic response to intracerebroventricular injection.

Keywords: Exendin-3 (9–39), Ex9; cFos; meal patterns.

Figures

Fig. 1.
Fig. 1.
Average daily 1-h LD intake (volume on y-axis, % body wt indicated at each data point) by all rats (n = 29) during 5 days of acclimation to scheduled feeding (meal entrainment) and by rats in each subgroup on the final testing day (day 6). There was no significant difference in 1-h intake on acclimation days 4 and 5 (paired-samples t-test, P > 0.05), evidence that intakes had stabilized. On day 6, rats were randomly assigned to 1 of 5 feeding groups (n = 5–7 per group, as indicated), and the average amount of diet consumed by rats within each group is indicated (by different symbols). LD, standard liquid diet; EN, Ensure; diEN, diluted Ensure; RES-LD, restricted LD; NF, not fed; BW, body weight.
Fig. 2.
Fig. 2.
Proportion (%) of glucagon-like peptide (GLP)-1-immunopositive neurons within the caudal nucleus of the solitary tract (cNST, filled bars) and medullary reticular formation (MRF, open bars) activated to express cFos in rats consuming final test meals of different sizes or types. Within each regional subgroup of GLP-1 neurons, bars with different letters (A, B, C for the cNST; a, b for the MRF) are significantly different between feeding condition groups (P < 0.05). LD, standard liquid diet; EN, Ensure; diEN, diluted Ensure; RES-LD, restricted LD; NF, not fed.
Fig. 3.
Fig. 3.
GLP-1-positive (brown cytoplasmic labeling, B) neurons within the cNST (region indicated by black arrow in A) are activated to express cFos (black nuclear labeling, B) in a representative rat that consumed 14% of its body weight in LD. The white arrow in A indicates the MRF, where GLP-1-positive neurons also reside. Black arrows in B point out some of the double-labeled neurons in which nuclear cFos immunolabeling is colocalized with cytoplasmic GLP-1. Scale bar in B = 25 μm. Brain stem schematic in A, 14.3 mm caudal to bregma (adapted from Ref. , available by CC BY-NC 4.0, https://creativecommons.org/licenses/by-nc/4.0/).
Fig. 4.
Fig. 4.
Relationship between amount consumed and cNST GLP-1 neuronal activation in meal-entrained rats consuming different liquid diets for 1 h. Each symbol represents data from 1 rat. Data points (Xs) from our previously published report using food deprived, nonentrained rats (23) are added for comparison (“Nonentrained: EN”). Data points from Entrained: NF rats are plotted for comparison, but the indicated correlation value is derived only from the 5 fed groups.
Fig. 5.
Fig. 5.
Daily food intake (expressed as kcal) during the scheduled feeding acclimation period for rats with intracerebroventricular cannulas (experiment 2). Data from all 24 rats are represented for each day (except for 1 rat with missing data on days 1 and 2, n = 23 on those days). Values within the gray bars indicate Ensure intake expressed as % body weight on that day. Open bars depict post-Ensure overnight chow intake.
Fig. 6.
Fig. 6.
Two-hour Ensure intake (expressed as % body wt) from each rat within the NaCl vehicle (SAL)-assigned group (left, n = 12) and the Exendin-3(9–39) (Ex9)-assigned group (right, n = 12) is depicted on baseline day (day 6) and on intracerebroventricular injection day (day 7).
Fig. 7.
Fig. 7.
Cumulative 2-h Ensure intake in ad libitum-fed, meal-entrained rats (experiment 2). A: the between-groups comparison of cumulative intake (as % body wt) by intracerebroventricular SAL- vs. Ex9-injected rats (day 7), with group means adjusted for baseline intake on the previous noninjection day (day 6) (ANCOVA, *P < 0.05). In B, cumulative 2 h intake on the intracerebroventricular injection day is normalized to each rat's own baseline intake and then averaged within each intracerebroventricular injection group (t-test, *P < 0.05).

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