Ghrelin modulates the fMRI BOLD response of homeostatic and hedonic brain centers regulating energy balance in the rat.

Miklós Sárvári,Levente Deli,Zsolt Liposits,Nikolett Hegedűs,Szabolcs Dávid,Dávid Gajári,Károly Tihanyi,Zsófia Pozsgay,Pál Kocsis

doi:10.1371/journal.pone.0097651

Abstract

The orexigenic gut-brain peptide, ghrelin and its G-protein coupled receptor, the growth hormone secretagogue receptor 1a (GHS-R1A) are pivotal regulators of hypothalamic feeding centers and reward processing neuronal circuits of the brain. These systems operate in a cooperative manner and receive a wide array of neuronal hormone/transmitter messages and metabolic signals. Functional magnetic resonance imaging was employed in the current study to map BOLD responses to ghrelin in different brain regions with special reference on homeostatic and hedonic regulatory centers of energy balance. Experimental groups involved male, ovariectomized female and ovariectomized estradiol-replaced rats. Putative modulation of ghrelin signaling by endocannabinoids was also studied. Ghrelin-evoked effects were calculated as mean of the BOLD responses 30 minutes after administration. In the male rat, ghrelin evoked a slowly decreasing BOLD response in all studied regions of interest (ROI) within the limbic system. This effect was antagonized by pretreatment with GHS-R1A antagonist JMV2959. The comparison of ghrelin effects in the presence or absence of JMV2959 in individual ROIs revealed significant changes in the prefrontal cortex, nucleus accumbens of the telencephalon, and also within hypothalamic centers like the lateral hypothalamus, ventromedial nucleus, paraventricular nucleus and suprachiasmatic nucleus. In the female rat, the ghrelin effects were almost identical to those observed in males. Ovariectomy and chronic estradiol replacement had no effect on the BOLD response. Inhibition of the endocannabinoid signaling by rimonabant significantly attenuated the response of the nucleus accumbens and septum. In summary, ghrelin can modulate hypothalamic and mesolimbic structures controlling energy balance in both sexes. The endocannabinoid signaling system contributes to the manifestation of ghrelin's BOLD effect in a region specific manner. In females, the estradiol milieu does not influence the BOLD response to ghrelin.

Highlights

The hunger signal ghrelin [1] is a potent orexigenic hormone [2] that acts via its G-protein coupled receptor, growth hormone secretagogue receptor 1a (GHS-R1A) [3] within the central nervous system
Homeostatic feeding centers of the hypothalamus were represented by the arcuate nucleus, ventromedial nucleus, dorsomedial nucleus, paraventricular nucleus, lateral hypothalamus and the circadian rhythm generator suprachiasmatic nucleus
We explored the BOLD effects of peripherally administered ghrelin in hedonic and homeostatic centers regulating energy balance in the rat using fMRI

Summary

Introduction

The hunger signal ghrelin [1] is a potent orexigenic hormone [2] that acts via its G-protein coupled receptor, GHS-R1A [3] within the central nervous system. The preganglionic neurons of parasympathetic centers in the brainstem, hypothalamic nuclei with longstanding history of contribution to regulation of feeding and energy expenditure, the hippocampal formation and the dopaminergic mesostriatal and mesolimbic systems arising from the rostral mesencephalon are primary targets of direct, receptor-mediated signaling of ghrelin. The binding of radiolabeled ghrelin to identical, GHS-R1A containing loci proves the expression and functional capacity of the receptor protein [6]. In addition to the stomach [7], which provides the major ghrelin supply for the brain, the production of ghrelin in a discrete set of hypothalamic neurons has been shown [8]. Ghrelin-immunoreactive axons have been detected in rodent [8,9] and post-mortem human [10] brains

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