On the central mechanism underlying ghrelin's chronic pro-obesity effects in rats: new insights from studies exploiting a potent ghrelin receptor antagonist.
In the present study, we explore the central nervous system mechanism underlying the chronic central effects of ghrelin with respect to increasing body weight and body fat. Specifically, using a recently developed ghrelin receptor antagonist, GHS-R1A (JMV2959), we investigate the role of GHS-R1A in mediating the effects of ghrelin on energy balance and on hypothalamic gene expression. As expected, in adult male rats, chronic central treatment with ghrelin for 14 days, when compared to vehicle-treated control rats, resulted in an increased body weight, lean mass and fat mass (assessed by dual X-ray absorptiometry), dissected white fat pad weight, cumulative food intake, food efficiency, respiratory exchange ratio and a decrease of energy expenditure. Co-administration of the ghrelin receptor antagonist JMV2959 suppressed/blocked the majority of these effects, with the notable exception of ghrelin-induced food intake and food efficiency. The hypothesis emerging from these data, namely that GHS-R1A mediates the chronic effects of ghrelin on fat accumulation, at least partly independent of food intake, is discussed in light of the accompanying data regarding the hypothalamic genes coding for peptides and receptors involved in energy balance regulation, which were found to have altered expression in these studies.
Salomé
N
N
Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden. nicolas.salome@genfit.com
Hansson
C
C
Taube
M
M
Gustafsson-Ericson
L
L
Egecioglu
E
E
Karlsson-Lindahl
L
L
Fehrentz
J A
JA
Martinez
J
J
Perrissoud
D
D
Dickson
S L
SL
D000818:Animals; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004435:Eating / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D054439:Ghrelin / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology*; D006728:Hormones / Q000097:blood; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D009765:Obesity / Q000097:blood / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
D054439:Ghrelin; D006727:Hormone Antagonists; D006728:Hormones; D054440:Receptors, Ghrelin