Hyperphagic Effects of Brainstem Ghrelin Administration

Abstract

The role of ghrelin in feeding control has been addressed from a largely hypothalamic perspective, with little attention directed at ingestive consequences of stimulation of the peptide's receptor, the growth hormone secretagogue receptor (GHS-R), in the caudal brainstem. Here, we demonstrate a hyperphagic response to stimulation of GHS-R in the caudal brainstem. Ghrelin (150 pmol) delivered to the third and fourth ventricles significantly and comparably increased cumulative food intake, with maximal response ϳ3 h after injection. The meal patterning effects underlying this hyperphagia were also similar for the two placements (i.e., significant reduction in the time between injection and first-meal onset, an increase in the number of meals taken shortly after the injection, and a trend toward an increase in the average size of the first meals that approached but did not achieve statistical significance). In a separate experiment, ghrelin microinjected unilaterally into the dorsal vagal complex (DVC) significantly increased food intake measured 1.5 and 3 h after treatment. The response was obtained with a 10-pmol dose, establishing the DVC as a site of action with at least comparable sensitivity to that reported for the arcuate nucleus. Taken together, the results affirm a caudal brainstem site of action and recommend further investigation into multisite interactions underlying the modulation of ingestive behavior by ghrelin. Diabetes 52: 2260 -2265, 2003 G hrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) (1), is secreted primarily from the gastrointestinal tract (2) and induces a hyperphagic response when delivered centrally via lateral or third intracerebroventricular injection (3-6). The arcuate nucleus of the hypothalamus (ARC) has been taken as the principal central site of ghrelin action because of 1) the abundance of GHS-R in this structure (7), 2) the expression of GHS-R in almost all ARC neuropeptide Y/agouti-related protein neurons (8), which are considered important in the downstream mediation of various peripherally and centrally stimulated effects on feeding and energy balance (9), 3) a variety of evidence indicating the functional significance of ghrelin action on neuropeptide Y/agouti-related protein neurons (4,6,10,11), and 4) the hyperphagic response obtained upon injection of doses as low as 30 pmol to this structure (12). At the same time, however, it is important to note that central nervous system GHS-R expression is not limited to the ARC (7) and that other structures relevant to feeding control, some of which are outside the hypothalamus, may also contribute to pharmacological and physiological actions of ghrelin.GHS-Rs are clearly represented in the caudal brainstem (7,13), although the anatomical extent of the distribution has not yet been fully described. Least studied in this regard are medullary sites, such as the dorsal vagal complex (DVC), which are clearly relevant to the neural control of feeding behavior. A recent study by J.M. Zigman and J.K. Elmq...

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