Novel Regulator of Acylated Ghrelin, CF801, Reduces Weight Gain, Rebound Feeding after a Fast, and Adiposity in Mice

Abstract

Ghrelin is a 28 amino acid hormonal peptide that is intimately related to the regulation of food intake and body weight. Once secreted, ghrelin binds to the growth hormone secretagogue receptor-1a, the only known receptor for ghrelin and is capable of activating a number of signaling cascades, ultimately resulting in an increase in food intake and adiposity. Because ghrelin has been linked to overeating and the development of obesity, a number of pharmacological interventions have been generated in order to interfere with either the activation of ghrelin or interrupting ghrelin signaling as a means to reducing appetite and decrease weight gain. Here, we present a novel peptide, CF801, capable of reducing circulating acylated ghrelin levels and subsequent body weight gain and adiposity. To this end, we show that IP administration of CF801 is sufficient to reduce circulating plasma acylated ghrelin levels. Acutely, intraperitoneal injections of CF801 resulted in decreased rebound feeding after an overnight fast. When delivered chronically, they decreased weight gain and adiposity without affecting caloric intake. CF801, however, did cause a change in diet preference, decreasing preference for a high-fat diet and increasing preference for regular chow diet. Given the complexity of ghrelin receptor function, we propose that CF801, along with other compounds that regulate ghrelin secretion, may prove to be a beneficial tool in the study of the ghrelin system, and potential targets for ghrelin-based obesity treatments without altering the function of ghrelin receptors.

Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation

“…32, 64 The majority of in vitro assays for GOAT activity utilize the mouse isoform of GOAT (mGOAT) in either an enzyme- and cell-based format, 15, 30, 32, 33, 62, 65–69 with mGOAT and hGOAT exhibiting a high level of amino acid sequence homology (79% identity, 92% similarity; Figure 6). Only one example of a direct comparison of inhibitor potency between these closely related enzyme isoforms has been reported, with the [Dap 3 ]octanoyl-ghrelin (1–5)-NH 2 inhibitor exhibiting similar activity against hGOAT and mGOAT.…”

“…Only one example of a direct comparison of inhibitor potency between these closely related enzyme isoforms has been reported, with the [Dap 3 ]octanoyl-ghrelin (1–5)-NH 2 inhibitor exhibiting similar activity against hGOAT and mGOAT. 15, 30 As previously reported cell lines utilized to investigate ghrelin acylation and GOAT activity utilize mGOAT, 15, 32, 69, 70 the ability of these synthetic triterpenoids to inhibit mGOAT must be established at the enzyme level prior to cell-based studies.…”

“…15, 31, 52 For each assay, membrane fraction from Sf9 cells expressing hGOAT or mGOAT was thawed on ice and passed through an 18-gauge needle 10 times to homogenize. Assays were performed with ~100 μg of membrane protein, as determined by Bradford assay.…”

The octanoylated energy regulating hormone ghrelin: An expanded view of ghrelin’s biological interactions and avenues for controlling ghrelin signaling

“…In another approach to develop an agent capable of lowering ghrelin levels in circulation, Wellman and co-workers designed the desacyl ghrelin analog CF801 (Figure 3) (Wellman et al, 2015). This analog consists of the first 10 amino acids of ghrelin with an alanine mutation at the octanoylation site and an attached Tat sequence to enable cell permeability.…”

Ghrelin-axis function in the context of Adult Hippocampal Neurogenesis

“…HD CF801 treated mice had reduced fat mass and body weight gain, and attenuated inclination for high-fat food. Also, CF801 treated SG-1 cells, that are derived from stomach ghrelinomas, had reduced AG release (Wellman et al, 2015).…”