Distribution of glucagon-like peptide-1 immunoreactivity in the hypothalamic paraventricular and supraoptic nuclei

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Abstract

Glucagon-like peptide-1 (GLP-1) plays a role in modulating neuroendocrine and autonomic function. The hypothalamic paraventricular nucleus (PVN) contains aggregations of GLP-1 fibers and expresses GLP-1 receptors, making it a likely site of action for GLP-1 signaling. The current study was designed to establish domains of GLP-1 action, focusing on axosomatic appositions on different neuroendocrine and autonomic cell populations in the PVN. The data indicate abundant GLP-1-immunoreactive terminal appositions on corticotropin-releasing hormone neurons in the medial parvocellular PVN. GLP-1 positive boutons can also be observed in apposition to oxytocinergic neurons and on retrogradely labeled pre-autonomic neurons projecting to the region of the nucleus of the solitary tract. In contrast, there were very few vasopressinergic neurons with GLP-1 appositions. Overall, the data indicate that the central GLP-1 system preferentially targets neurons in hypophysiotrophic zones of the PVN, consistent with excitatory actions of GLP-1 on adrenocorticotropin release. GLP-1 is also in position to influence oxytocin secretion and control outflow to brainstem cardiovascular relays.

Introduction

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the intestine by nutrient signals, in particular, glucose ingestion (Kieffer and Habener, 1999). Like many ‘gut’ peptides, GLP-1 is also expressed in brain. Expression of GLP-1 is largely confined to groups of cells in the nucleus of solitary tract (NTS) and ventrolateral medulla of the brainstem (Larsen et al., 1997a, Larsen et al., 1997b). These neurons send GLP-1-immunoreactive axons and terminals to numerous regions of the brain, including regions responsible for integration of neuroendocrine stress responses (paraventricular nucleus) and energy balance (arcuate nucleus) (Drucker, 1990, Larsen et al., 1997a, Larsen et al., 1997b, Sarkar et al., 2003). The GLP-1 receptor (GLP-1R) is expressed in regions in receipt of GLP-1 fibers, including the PVN, the periventricular hypothalamus, the dorsomedial hypothalamus (DMH), and the arcuate nucleus (Arc) (Merchenthaler et al., 1999, Shughrue et al., 1996, Tang-Christensen et al., 2001).

Taken together, the distribution of GLP-1 and its receptor in brain suggests that central GLP-1 is functioning as a neurotransmitter/neuromodulator in neuroendocrine regulatory systems. This hypothesis is supported by functional data indicating a role for GLP-1 in ingestion and hypothalamo-pituitary-adrenocortical (HPA) axis function. Centrally infused GLP-1 elicits dose dependent suppression of food intake (Navarro et al., 1996, Tang-Christensen et al., 1996, Turton et al., 1996) that may be related to visceral signaling associated with food consumption (Vrang et al., 2003). In addition to its anorectic effects, GLP-1 also activates the hypothalamo-pituitary-adrenal (HPA) stress axis. Intracerebroventricular infusion of GLP-1 stimulates ACTH and/or corticosterone release (Kinzig et al., 2003, Larsen et al., 1997a, Larsen et al., 1997b). Induction of visceral illness by peripheral injections of lithium chloride (LiCl) activates GLP-1 expressing neurons in the NTS and the dorsomedial parvocellular region of the PVN (presumably CRH expressing neurons) (Rinaman, 1999). Importantly, the HPA response to LiCl is blocked by pre-administration of the GLP-1 antagonist des-His1, Glu8-exendin-4 (dHG-exendin) (Kinzig et al., 2003), suggesting that NTS GLP-1 is responsible for HPA activation induced by this stimulus. Anatomical data indicate that GLP-1 neurons from the NTS innervate the PVN (Larsen et al., 1997a, Larsen et al., 1997b, Rinaman, 1999), and form synaptic contacts with CRH-immunoreactive neurons (Sarkar et al., 2003), further consistent with a direct role for GLP-1 in HPA axis signaling. Finally, central GLP-1 increases blood pressure and heart rate, and activates brainstem neurons projecting to sympathetic preganglionic neurons, indicative of stimulatory effects of GLP-1 on the sympathetic nervous system (Yamamoto et al., 2002).

The data to date imply an important connection between medullary GLP-1 neurons and CRH neurons in the PVN. However, the PVN is an anatomically heterogeneous region, including several subtypes of neurons. In addition to parvocellular CRH neurons, this nucleus contains (1) magnocellular arginine vasopressin neurons projecting to the posterior pituitary; (2) magnocellular oxytocin neurons projecting to the posterior pituitary; and (3) parvocellular pre-autonomic neurons projecting to brainstem and spinal cord sites controlling cardiovascular function and sympathetic/parasympathetic activation (Swanson and Kuypers, 1980). Given diverse physiological actions of central GLP-1, it is important to determine the anatomical relationships between GLP-1 projections and the various functional components of PVN. Therefore, the current study was designed to assess anatomical interactions between GLP-1-immunoreactive fibers and various neural subtypes in the PVN and SON.

Section snippets

Materials and methods

Rats (Sprague–Dawley or Long-Evans) were acquired from Harlan Labs (Indianapolis, IN). All animals were triply housed in a temperature- and humidity-controlled facility at the University of Cincinnati, on a 6 a.m. to 6 p.m. light–dark cycle with free access to standard chow and water. All experimental procedures were approved by the University of Cincinnati Institutional Animal Care and Use Committee.

Results

As can be seen in Fig. 1A–D, GLP-1 fibers were distributed in medial parvocellular and dorsal parvocellular zones of the PVN, corresponding to median eminence and brainstem/spinal cord-projecting cell populations, respectively. GLP-1 positive fibers were also observed in oxytocin-rich divisions of the PVN, including the rostral posterior magnocellular division of the PVN and the ventral aspect of the medial parvocellular PVN. In contrast, GLP-1 fibers did not heavily invest AVP-enriched PVN

Discussion

The current study documents close appositions between GLP-1 terminals and oxytocin neurons in all magnocellular PVN subdivisions and in SON, consistent with the potential for synaptic interactions. Medial parvocellular CRH neurons and to a lesser extent, vasopressin neurons also appeared to be apposed by GLP-1 boutons. In contrast, there were few GLP-1 appositions on magnocellular vasopressin neurons. Together, the data suggest that GLP-1 neurons innervate oxytocin as well as CRH neurons, and

Acknowledgement

Funded by National Institute of Mental Health; Grant Number MH069680.

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