Acylation Type Determines Ghrelin's Effects on Energy Homeostasis in Rodents

Abstract

Ghrelin is a gastrointestinal polypeptide that acts through the ghrelin receptor (GHSR) to promote food intake and increase adiposity. Activation of GHSR requires the presence of a fatty-acid (FA) side chain on amino acid residue serine 3 of the ghrelin molecule. However, little is known about the role that the type of FA used for acylation plays in the biological action of ghrelin. We therefore evaluated a series of differentially acylated peptides to determine whether alterations in length or stability of the FA side chain have an impact on the ability of ghrelin to activate GHSR in vitro or to differentially alter food intake, body weight, and body composition in vivo. Fatty acids principally available in the diet (such as palmitate C16) and therefore representing potential substrates for the ghrelin-activating enzyme ghrelin O-acyltransferase (GOAT) were used for dose-, time-, and administration/route-dependent effects of ghrelin on food intake, body weight, and body composition in rats and mice. Our data demonstrate that altering the length of the FA side chain of ghrelin results in the differential activation of GHSR. Additionally, we found that acylation of ghrelin with a long-chain FA (C16) delays the acute central stimulation of food intake. Lastly, we found that, depending on acylation length, systemic and central chronic actions of ghrelin on adiposity can be enhanced or reduced. Together our data suggest that modification of the FA side-chain length can be a novel approach to modulate the efficacy of pharmacologically administered ghrelin.

GLP-1R Signaling Directly Activates Arcuate Nucleus Kisspeptin Action in Brain Slices but Does not Rescue Luteinizing Hormone Inhibition in Ovariectomized Mice During Negative Energy Balance

“…One week later, animals were stereotaxically implanted (David Kopf Instruments) with a cannula (brain infusion kit #3, Alzet) placed in the lateral cerebral ventricle as previously described (Heppner et al, 2012). A polyethylene catheter attached the cannula to an osmotic minipump (1007D, Alzet) that was subcutaneously implanted.…”

Uroguanylin levels in intestine and plasma are regulated by nutritional status in a leptin-dependent manner

“…In the intestine, the large list of hormones include gastrin, cholecystokinin, oxyntomodulin, glucagon-like peptide one and peptide YY [2], all of which act as anorectic agents. In the stomach, among other hormones, there is also ghrelin [3][4][5][6], the only one peptidic hormone that stimulates food intake and adiposity [7].…”

Food as a Hormone

“…However, for ghrelin to signal effectively, a fatty acid must first be attached to the peptide as a side chain. Different fatty acid side chains derived from different dietary fats change the ability of ghrelin to increase food intake (9). These fatty acid side chains come from ingested food rather than from adipose tissue (10).…”