Elsevier

Peptides

Volume 24, Issue 6, June 2003, Pages 919-923
Peptides

Hypothalamic paraventricular injections of ghrelin: effect on feeding and c-Fos immunoreactivity

https://doi.org/10.1016/S0196-9781(03)00159-1Get rights and content

Abstract

The paraventricular hypothalamic nucleus (PVN) appears to integrate orexigenic properties of a novel peptide, ghrelin. Thus, we examined central mechanisms underlying feeding generated by intra-PVN ghrelin. We established that 0.03 nmol of PVN-injected ghrelin was the lowest dose increasing food consumption and it induced c-Fos immunoreactivity (a marker of neuronal activation) in the PVN itself, as well as in other feeding-related brain areas, including the hypothalamic arcuate and dorsomedial nuclei, central nucleus of the amygdala, and nucleus of the solitary tract. We conclude that the PVN, as part of larger central circuitry, mediates orexigenic properties of ghrelin.

Introduction

Ghrelin, a novel 28-amino acid peptide, is synthesized in the periphery (stomach) [7], [12] and in the brain [12], [15], and is capable of crossing the blood brain barrier [3]. It acts as an endogenous ligand of the growth hormone secretagogue (GHS) receptor [9]. Aside from the initially studied function of this peptide as a GHS [1], [6], [9], recent studies have consistently shown that ghrelin is a potent inducer of food consumption [5], [14], [18], [28], [29]. It has been found that circulating levels of ghrelin increase following a 48-h fast, and infusion of glucose into the stomach decreases plasma-ghrelin concentration [28]. Also, ghrelin is released shortly before a meal in schedule-fed animals [24].

The organization of central circuitry appears to play an important role in integrating orexigenic effects of ghrelin. Perikarya synthesizing this peptide are localized in the hypothalamic arcuate nucleus (ARC) [12], [15] and project to brain sites involved in feeding regulation that contain the GHS receptor [8], [9], [17]. The few studies published thus far, have indicated that the paraventricular nucleus of the hypothalamus (PVN), as part of a larger feeding-related neural network, appears to mediate orexigenic properties of ghrelin. The PVN, which receives ARC-derived innervation [10], contains the GHS receptor [17], [30]. Direct injection of ghrelin into this site generates a robust feeding response [16], [29]. In addition, intracerebroventricularly (i.c.v.) administered ghrelin has been reported to increase c-Fos immunoreactivity (IR), a marker of neuronal activation, in the PVN and other brain regions such as the ARC, dorsomedial hypothalamic nucleus (DMH), lateral hypothalamus (LH), nucleus of the solitary tract (NTS) and area postrema (AP) [14], [18].

Based on the above, we hypothesized that direct injection of ghrelin into the PVN would not only robustly stimulate feeding, but would also “activate” the PVN, as well as other brain regions that are part of the feeding-related central circuitry. Thus, we infused ghrelin into the PVN and measured food intake and also assessed c-Fos IR levels in a variety of brain sites involved in the regulation of consummatory behavior.

Section snippets

Animals

Adult male Sprague–Dawley rats (Charles Rivers Laboratories, Wilmington, MA) weighing approximately 300 g at the beginning of the experiment were used in the studies. Animals were housed individually in wire-mesh cages with a 12:12 LD schedule (lights on at 07:00) in a temperature (21 °C) and humidity-controlled facility. Food (Rodent Chow, Teklad, Indianapolis, IN) and tap water were available ad libitum except when stated otherwise.

Surgeries

Rats were equipped with an indwelling stainless steel cannula

Results

Administration of 0.03 and 0.3 nmol ghrelin into the PVN resulted in an increase in feeding by approximately 1.25 g (P=0.0079) and 1.75 g (P=0.0004), respectively, during the first hour post-injection. During the second hour, only animals treated with the highest dose of the peptide consumed significantly more chow than controls (P=0.0267). No dose of the peptide affected 2–4 h consumption. In addition, cumulative 0–4 h food intake was significantly higher in rats treated with 0.3 nmol ghrelin

Discussion

Recently published data have implicated central nervous system circuitry in the mediation of ghrelin’s orexigenic effect. The few extant injection studies demonstrate the role of the hypothalamus in ghrelin-induced hyperphagia [14], [16], [18], [26], [29]. Within this central structure, the PVN is an area of crucial importance in energy metabolism (for review, see Ref. [11]). Our current data demonstrate that direct injection of ghrelin into the PVN (0.03 and 0.3 nmol) results in a short-lived,

Acknowledgements

This project was supported by NIH, National Research Service Award T32DA07097 from the National Institute of Drug Abuse, by the Department of Veterans Affairs, by the National Institute of Drug abuse Grant DA-03999, and by the National Institutes of Diabetes and Digestive and Kidney Disease Grant DK-42698 and P30 DK-50456.

References (30)

  • E. Arvat et al.

    Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone

    J. Clin. Endocrinol. Metab.

    (2001)
  • W.A. Banks et al.

    Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure

    J. Pharmacol. Exp. Ther.

    (2002)
  • C.J. Billington et al.

    Neuropeptide Y in hypothalamic paraventricular nucleus: a center coordinating energy metabolism

    Am. J. Physiol.

    (1994)
  • D.E. Cummings et al.

    A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans

    Diabetes

    (2001)
  • A.D. Howard et al.

    A receptor in pituitary and hypothalamus that functions in growth hormone release

    Science

    (1996)
  • Cited by (101)

    • Effects of opioid receptor ligands in rats trained to discriminate 22 from 2 hours of food deprivation suggest a lack of opioid involvement in eating for hunger

      2020, Behavioural Brain Research
      Citation Excerpt :

      PVN perfusions with NPY result in dramatic increases in food intake [29], and PVN NPY-treated rats (unlike DAMGO-injected animals) given a choice between calorie-dense and bland chow versus calorie-dilute and palatable sucrose solution, shift their preference towards chow [30]. Similarly to NPY, central ghrelin increases consumption of “bland” diets, such as a cornstarch mix [1,31–34]. Plasma ghrelin levels are elevated after a fast and decrease upon glucose stomach infusions [35].

    • Lateral Hypothalamic Control of Sleep in the Context of Cancer

      2020, Neurological Modulation of Sleep: Mechanisms and Function of Sleep Health
    View all citing articles on Scopus
    View full text