Abstract
ObjectiveGhrelin acylation by ghrelin O-acyltransferase (GOAT) has recently been reported to be essential for the prevention of hypoglycemia during prolonged negative energy balance. Using a unique set of four different genetic loss-of-function models for the GOAT/ghrelin/growth hormone secretagogue receptor (GHSR) system, we thoroughly tested the hypothesis that lack-of-ghrelin activation or signaling would lead to hypoglycemia during caloric deprivation.MethodologyMale and female knockout (KO) mice for GOAT, ghrelin, GHSR, or both ghrelin and GHSR (dKO) were subjected to prolonged calorie restriction (40% of ad libitum chow intake). Body weight, fat mass, and glucose levels were recorded daily and compared to wildtype (WT) controls. Forty-eight hour blood glucose profiles were generated for each individual mouse when 2% or less body fat mass was reached. Blood samples were obtained for analysis of circulating levels of acyl- and desacyl-ghrelin, IGF-1, and insulin.Principal FindingsChronic calorie restriction progressively decreased body weight and body fat mass in all mice regardless of genotype. When fat mass was depleted to 2% or less of body weight for 2 consecutive days, random hypoglycemic events occurred in some mice across all genotypes. There was no increase in the incidence of hypoglycemia in any of the four loss-of-function models for ghrelin signaling including GOAT KO mice. Furthermore, no differences in insulin or IGF-1 levels were observed between genotypes.ConclusionThe endogenous GOAT-ghrelin-GHSR system is not essential for the maintenance of euglycemia during prolonged calorie restriction.
Highlights
Ghrelin is a 28 amino acid polypeptide with a fatty acid esterified to its serine-3 residue [1]
When calories were restricted to 40% of ad libitum food intake, WT, ghrelin O-acyl transferase (GOAT) KO, ghrelin KO, growth hormone secretagogue receptor (GHSR) KO and ghrelin-GHSR dKO mice showed a consistent decrease in body weight (BW) (Figures 1A, 1C and S1A, S1C, left panels) and fat mass (Figures 1B, 1D and S1B, S1D, right panels)
Regardless of genotypes, the rate of fat mass loss in female mice was less rapid under CR (Figures 1D and S1D) as compared to their male counterparts, allowing female mice to persist longer on the CR regime
Summary
Ghrelin is a 28 amino acid polypeptide with a fatty acid esterified to its serine-3 residue [1]. Such esterification, catalyzed by the enzyme ghrelin O-acyl transferase (GOAT) [2,3], is essential to activate the only known ghrelin receptor (GHSR) [4]. Acyl-ghrelin has been shown to inhibit insulin secretion in rodents [6] and humans [7]. Desacyl-ghrelin has been shown to have either no effect [8], or beneficial effects on insulin sensitivity [9] and insulin secretion [10]. Desacyl- and acyl-ghrelin might be endogenous opponents in systemic regulation of glucose metabolism [11]
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