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Comparative Study
. 2008 Aug;149(8):4059-68.
doi: 10.1210/en.2007-1743. Epub 2008 Apr 17.

Caudal brainstem processing is sufficient for behavioral, sympathetic, and parasympathetic responses driven by peripheral and hindbrain glucagon-like-peptide-1 receptor stimulation

Matthew R Hayes  1 , Karolina P Skibicka, Harvey J Grill
Affiliations
Comparative Study

Caudal brainstem processing is sufficient for behavioral, sympathetic, and parasympathetic responses driven by peripheral and hindbrain glucagon-like-peptide-1 receptor stimulation

Matthew R Hayes et al. Endocrinology. 2008 Aug.

Abstract

The effects of peripheral glucagon like peptide-1 receptor (GLP-1R) stimulation on feeding, gastric emptying, and energetic responses involve vagal transmission and central nervous system processing. Despite a lack of studies aimed at determining which central nervous system regions are critical for the GLP-1R response production, hypothalamic/forebrain processing is regarded as essential for these effects. Here the contribution of the caudal brainstem to the control of food intake, core temperature, heart rate, and gastric emptying responses generated by peripheral delivery of the GLP-1R agonist, exendin-4 (Ex-4), was assessed by comparing responses of chronic supracollicular decerebrate (CD) rats to those of pair-fed intact control rats. Responses driven by hindbrain intracerebroventricular (fourth i.c.v) delivery of Ex-4 were also evaluated. Intraperitoneal Ex-4 (1.2 and 3.0 microg/kg) suppressed glucose intake in both CD rats (5.0+/-1.2 and 4.4+/-1.1 ml ingested) and controls (9.4+/-1.5 and 7.7+/-0.8 ml ingested), compared with intakes after vehicle injections (13.1+/-2.5 and 13.2+/-1.7 ml ingested, respectively). Hindbrain ventricular Ex-4 (0.3 microg) also suppressed food intake in CD rats (4.7+/-0.6 ml ingested) and controls (11.0+/-2.9 ml ingested), compared with vehicle intakes (9.3+/-2.1 and 19.3+/-4.3 ml ingested, respectively). Intraperitoneal Ex-4 (0.12, 1.2, 2.4 microg/kg) reduced gastric emptying rates in a dose-related manner similarly for both CD and control rats. Hypothermia followed ip and fourth i.c.v Ex-4 in awake, behaving controls (0.6 and 1.0 C average suppression) and CD rats (1.5 and 2.5 C average suppression). Intraperitoneal Ex-4 triggered tachycardia in both control and CD rats. Results demonstrate that caudal brainstem processing is sufficient for mediating the suppression of intake, core temperature, and gastric emptying rates as well as tachycardia triggered by peripheral GLP-1R activation and also hindbrain-delivered ligand. Contrary to the literature, hypothalamic/forebrain processing and forebrain-caudal brainstem communication is not required for the observed responses.

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Figures

Figure 1
Figure 1
Intraoral glucose (10%) intake (infused at 0.8 ml/min) for CD and control rats did not differ as a function of the neurological condition of the rat. Intraperitoneal Ex-4 at 1.2 and 3.0 μg/kg suppressed intake significantly in both control and CD rats, compared with respective vehicle intakes. The suppression of intake by peripheral Ex-4 did not differ as a function of the neurological condition of the rat (CD vs. control). *, P < 0.05 from respective vehicle.
Figure 2
Figure 2
Intraoral glucose (10%) intake for CD and control rats did not differ as a function of the neurological condition of the rat. Fourth icv administration of Ex-4 (0.3 μg) significantly suppressed intakes in both control and CD rats, compared with respective aCSF vehicle intakes. The suppression of intake by hindbrain ventricular Ex-4 did not differ as a function of the neurological condition of the rat (CD vs. control). *, P < 0.05 from respective vehicle.
Figure 3
Figure 3
For control and CD rats, ip administration of Ex-4 (1.2 and 2.4 μg/kg) significantly suppressed 5 min gastric emptying of 0.9% saline, compared with vehicle in similar fashions. The gastric-emptying rates for the vehicle condition was not statistically different between control and CD rats, indicating that forebrain processing and forebrain-caudal brainstem communication is not necessary for the control of basal gastric emptying. *, P < 0.05 from respective vehicle.
Figure 4
Figure 4
Tc (C) in control and CD rats before and after injection of fourth icv Ex-4 (0.3 μg), ip Ex-4 (3.0 μg/kg), or vehicle. Across-rat averaged Tc throughout the 6.5-h period after injections in control (A) and CD (B) rats. The histograms (C) represent 6.5-h averages of Tc and show significant hypothermia after both fourth icv and ip Ex-4 administration for control and CD rats. *, P < 0.05 from respective vehicle Tc.
Figure 5
Figure 5
HR (BPM) in control and CD rats before and after injection of fourth icv Ex-4 (0.3 μg), ip Ex-4 (3.0 μg/kg), or vehicle. Across-rat averaged HR throughout the 6.5-h period after injections in control (A) and CD (B) rats is shown. The histogram (C) represents 6.5-h averages of HR and shows elevated HR in response to fourth icv Ex-4 injections. After ip Ex-4, HR was significantly elevated in control rats, compared with HRs after vehicle injection, whereas CD rats showed a nonsignificant increase in HR after ip Ex-4. *, P < 0.05 from respective vehicle heart rate.
Figure 6
Figure 6
Spontaneous activity (counts) in control (A) and CD (B) rats before and after injection of fourth icv Ex-4 (0.3 μg), ip Ex-4 (3.0 μg/kg), or vehicle. The histogram (C) represents 6.5-h averages for spontaneous activity counts. Control rats showed no significant alteration in spontaneous activity after Ex-4 administration. Activity counts after vehicle injection for CD rats were significantly greater than for control rats. This difference in vehicle values rather than differences for the ip and fourth icv Ex-4 conditions between CD and control rats contributes to the group differences observed. *, P < 0.05 from respective vehicle activity counts.
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