The opposing effects of ghrelin on hypothalamic and systemic inflammatory processes are modulated by its acylation status and food intake in male rats.
Ghrelin is an endogenous hormone that stimulates appetite and adipose tissue accrual. Both the acylated (AG) and non-acylated (DAG) isoforms of this hormone are also reported to exert anti-inflammatory and protective effects systemically and in the central nervous system. As inflammatory processes have been implicated in obesity-associated secondary complications, we hypothesized that this natural appetite stimulator may protect against negative consequences resulting from excessive food intake. Adult male Wistar rats were treated icv (5 μg/day) with AG, DAG, the ghrelin mimetic GH-releasing peptide (GHRP)-6, AG, and pair-fed with controls (AG-pf) or saline for 14 days. Regardless of food intake AG increased visceral adipose tissue (VAT) and decreased circulating cytokine levels. However, AG reduced cytokine production in VAT only in rats fed ad libitum. Hypothalamic cytokine production was increased in AG-treated rats fed ad libitum and by DAG, but intracellular inflammatory signaling pathways associated with insulin and leptin resistance were unaffected. Gliosis was not observed in response to any treatment as glial markers were either reduced or unaffected. AG, DAG, and GHRP-6 stimulated production of hypothalamic insulin like-growth factor I that is involved in cell protective mechanisms. In hypothalamic astrocyte cell cultures AG decreased tumor necrosis factorα and DAG decreased interleukin-1β mRNA levels, suggesting direct anti-inflammatory effects on astrocytes. Thus, whereas ghrelin stimulates food intake and weight gain, it may also induce mechanisms of cell protection that help to detour or delay systemic inflammatory responses and hypothalamic gliosis due to excess weight gain, as well as its associated pathologies.
Hospital Infantil Universitario Niño Jesús, Department of Endocrinology, Instituto de Investigación La Princesa, Universidad Autónoma de Madrid and Centro de Investigación Biomédica en Red (CIBER) de la Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 28009 Madrid, Spain.
Cristina
C
García-Cáceres
Esther
E
Fuente-Martín
Francisca
F
Díaz
Miriam
M
Granado
Pilar
P
Argente-Arizón
Laura M
LM
Frago
Alejandra
A
Freire-Regatillo
Vicente
V
Barrios
Jesús
J
Argente
Julie A
JA
Chowen
D000215:Acylation; D050154:Adiposity; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004435:Eating / Q000502:physiology*; D054439:Ghrelin / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015430:Weight Gain / Q000502:physiology*
D016207:Cytokines; D054439:Ghrelin; D018836:Inflammation Mediators; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I