title: Immunomodulatory actions of central ghrelin in diet-induced energy imbalance.
abstract: We investigated the effects of centrally administered orexigenic hormone ghrelin on energy imbalance-induced inflammation. Rats were subjected for four weeks to three different dietary regimes: normal (standard food), high-fat (standard food with 30% lard) or food-restricted (70%, 50%, 40% and 40% of the expected food intake in 1st, 2nd, 3rd and 4th week, respectively). Compared to normal-weight controls, starved, but not obese rats had significantly higher levels of proinflammatory cytokines (TNF, IL-1β, IFN-γ) in the blood. When compared to normally fed animals, the hearts of starved and obese animals expressed higher levels of mRNAs encoding proinflammatory mediators (TNF, IL-1β, IL-6, IFN-γ, IL-17, IL-12, iNOS), while mRNA levels of the anti-inflammatory TGF-β remained unchanged. Intracerebroventricular (ICV) injection of ghrelin (1 μg/day) for five consecutive days significantly reduced TNF, IL-1β and IFN-γ levels in the blood of starved rats, as well as TNF, IL-17 and IL-12p40 mRNA expression in the hearts of obese rats. Conversely, ICV ghrelin increased the levels of IFN-γ, IL-17, IL-12p35 and IL-12p40 mRNA in the heart tissue of food-restricted animals. This was associated with an increase of immunosuppressive ACTH/corticosterone production in starved animals and a decrease of the immunostimulatory adipokine leptin both in food-restricted and high-fat groups. Ghrelin activated the energy sensor AMP-activated protein kinase (AMPK) in the hypothalamus and inhibited extracellular signal-regulated kinase (ERK) in the hearts of obese, but not starved rats. Therefore, central ghrelin may play a complex role in energy imbalance-induced inflammation by modulating HPA axis, leptin and AMPK/ERK signaling pathways.
authors.affiliation: Institute of Medical Physiology, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia. dstevanovic@med.bg.ac.rs
authors.forename: Darko
authors.initials: D
authors.lastname: Stevanovic
authors.forename: Vesna
authors.initials: V
authors.lastname: Starcevic
authors.forename: Urosh
authors.initials: U
authors.lastname: Vilimanovich
authors.forename: Dejan
authors.initials: D
authors.lastname: Nesic
authors.forename: Ljubica
authors.initials: L
authors.lastname: Vucicevic
authors.forename: Maja
authors.initials: M
authors.lastname: Misirkic
authors.forename: Kristina
authors.initials: K
authors.lastname: Janjetovic
authors.forename: Emina
authors.initials: E
authors.lastname: Savic
authors.forename: Dusan
authors.initials: D
authors.lastname: Popadic
authors.forename: Emina
authors.initials: E
authors.lastname: Sudar
authors.forename: Dragan
authors.initials: D
authors.lastname: Micic
authors.forename: Mirjana
authors.initials: M
authors.lastname: Sumarac-Dumanovic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trajkovic
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D031204:Caloric Restriction; D002490:Central Nervous System / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects* / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D054439:Ghrelin / Q000008:administration & dosage / Q000494:pharmacology*; D006728:Hormones / Q000378:metabolism; D007155:Immunologic Factors; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007276:Injections, Intraventricular; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D013217:Starvation / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D004041:Dietary Fats; D054439:Ghrelin; D006728:Hormones; D007155:Immunologic Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D000263:Adenylate Kinase