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. 2002 Jul;110(1):43-52.
doi: 10.1172/JCI15595.

Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons

Hiroshi Yamamoto  1 , Charlotte E Lee, Jacob N Marcus, Todd D Williams, J Michael Overton, Marisol E Lopez, Anthony N Hollenberg, Laurie Baggio, Clifford B Saper, Daniel J Drucker, Joel K Elmquist
Affiliations

Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons

Hiroshi Yamamoto et al. J Clin Invest. 2002 Jul.

Abstract

Glucagon-like peptide-1 (GLP-1) released from the gut functions as an incretin that stimulates insulin secretion. GLP-1 is also a brain neuropeptide that controls feeding and drinking behavior and gastric emptying and elicits neuroendocrine responses including development of conditioned taste aversion. Although GLP-1 receptor (GLP-1R) agonists are under development for the treatment of diabetes, GLP-1 administration may increase blood pressure and heart rate in vivo. We report here that centrally and peripherally administered GLP-1R agonists dose-dependently increased blood pressure and heart rate. GLP-1R activation induced c-fos expression in the adrenal medulla and neurons in autonomic control sites in the rat brain, including medullary catecholamine neurons providing input to sympathetic preganglionic neurons. Furthermore, GLP-1R agonists rapidly activated tyrosine hydroxylase transcription in brainstem catecholamine neurons. These findings suggest that the central GLP-1 system represents a regulator of sympathetic outflow leading to downstream activation of cardiovascular responses in vivo.

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Figures

Figure 1
Figure 1
Effects of i.c.v. or i.v. administration of EXN-4 on MAP and HR. Both i.v. EXN-4 (a and b) and i.c.v. EXN-4 (c and d) dose-dependently increase MAP (a and c) and HR (b and d). EXN-4 was injected at “0.” *P < 0.05, **P < 0.01.
Figure 2
Figure 2
Distribution of i.v. EXN-4–induced Fos-IR in the brain. A series of photomicrographs demonstrates Fos-IR in neurons 2 hours after i.v. administration of EXN-4 (first and third columns) or PFS (second and fourth columns) in several brain regions. These regions include (a and b) the paraventricular nucleus of the hypothalamus (PVH); (c and d) the lateral hypothalamic area (LHA); (e and f) the arcuate nucleus (Arc) and the retrochiasmatic area (RCA); (g and h) the external lateral subdivision of the parabrachial nucleus (PBel); (i and j) the locus coeruleus (LC); (k and l) the A5 cell group (A5); (m and n) the area postrema (AP) and the NTS; (o and p) the rostral ventrolateral medulla (RVML); (q and r) the caudal ventrolateral medulla (CVLM); and (s and t) the IML in the spinal cord. 3v, third ventricle; f, fornix; 4v, fourth ventricle; VII, facial nerve. Scale bar = 250 μm in a–d, g, and h, and 100 μm in e, f, and i–t.
Figure 3
Figure 3
Distribution of i.c.v. EXN-4–induced Fos-IR in the brain and the adrenal gland. A series of photomicrographs demonstrates Fos-IR in neurons 2 hours after i.c.v. administration of EXN-4 (a–t, first and third columns; v–x) or PFS (a–t, second and fourth columns; u) in several brain regions and the adrenal gland. The brain regions include (a and b) the PVH; (c and d) the LHA; (e and f) the Arc/RCA; (g and h) the PBel; (i and j) the LC; (k and l) the A5; (m and n) the AP and the NTS; (o and p) the RVML; (q and r) the CVLM; and (s and t) the IML in the spinal cord. In the adrenal gland, after administration of PFS, little Fos-IR is visible (u). After i.c.v. EXN-4 at subthreshold dose (v; 3 μg), a little Fos-IR is visible. In contrast, i.c.v. EXN-4 at threshold dose (w; 30 μg) or a higher dose (x; 300 μg) induces Fos-IR in the adrenal medulla. Note that at the higher dose (x), Fos-IR is also visible in the cortex. Scale bar = 500 μm in a–d, g, and h; 200 μm in e, f, and i–t; and 50 μm in u–x.
Figure 4
Figure 4
EXN-4–activated neurons projecting to the spinal cord. A series of line drawings demonstrates the distribution of Fos-IR (black circles), FG-IR (blue circles), and double-labeled (red stars) neurons in three rostral-to-caudal levels of the PVH (a–c), the Arc/RCA (d–f), and the LHA (g–i) of the hypothalamus after i.c.v. injection of EXN-4, in animals with FG injection into the spinal cord. Scale bar = 250 μm in a–c and 1,000 μm in d–i. Divisions of the PVH: dp, dorsal parvocellular; mp, medial parvocellular; pm, posterior magnocellular; vp, ventral parvocellular; lp, lateral parvicellular; ic, internal capsule. VMH, ventromedial nucleus of the hypothalamus; DMH, dorsomedial nucleus of the hypothalamus; ME, median eminence.
Figure 5
Figure 5
EXN-4 activates medullary catecholamine neurons projecting to the spinal cord. (a–c) Double-label immunohistochemistry demonstrates that neurons that innervate sympathetic preganglionic neurons (brown cytoplasm) also contain i.c.v. EXN-4–induced Fos-IR (black nuclei) in (a) the PVH, (b) the Arc/RCA, and (c) the LHA of the hypothalamus. (d–f) Higher-magnification view of the boxed areas in a–c, respectively. (g–i) Double-label immunohistochemistry demonstrates that TH-immunoreactive neurons (brown cytoplasm) also contain i.c.v. EXN-4–induced Fos-IR (black nuclei) in (g) the NTS, (h) the LC, and (i) the CVLM. (j–l) Higher-magnification view of the boxed areas in g–i, respectively. (m–p) Triple-label immunohistochemistry reveals that many medullary catecholamine neurons (red cytoplasm in m and o) that project to the IML in the spinal cord (green neurons in n and p) also contain i.c.v. EXN-4–induced Fos-IR (black nuclei) in the RVLM (m and n) and the A5 (o and p). Scale bar = 100 μm in a–c and g–i, 25 μm in d–f and j–l, and 50 μm in m–p.
Figure 6
Figure 6
Intracerebroventricular EXN-4 activates TH transcription in the medullary catecholamine neurons. All sections were hybridized with a specific TH intronic RNA probe 15 minutes after administration of i.c.v. EXN-4 (left column) or PFS (right column) in several brainstem regions, including (a and b) the LC, (c and d) the A5, (e and f) the RVLM, (g and h) the CVLM, and (i and j) the caudal part of the NTS. CC, central canal. Scale bar = 100 μm.
Figure 7
Figure 7
A neuroanatomical model of GLP-1’s actions in the rat brain. Circulating GLP-1 engages GLP-1Rs on the hypothalamic neurons in the PVH, Arc, and LHA, and medullary catecholamine neurons in the A5, RVLM, and CVLM, probably through the AP and NTS where GLP-1 neurons are located. These GLP-1–activated neurons in the hypothalamus and brainstem have monosynaptic descending projections to the sympathetic preganglionic neurons in the IML, which innervate the adrenal medulla and heart to increase BP and HR (autonomic responses). This model predicts that some of the medullary catecholamine neurons project to the hypothalamic neurons. GLP-1–activated neurons in the PVH also act on the pituitary to engage neuroendocrine responses.
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