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Yi, C.-X. ; Heppner, K.M.* ; Kirchner, H.* ; Tong, J.* ; Bielohuby, M.* ; Gaylinn, B.D.* ; Müller, T.D. ; Bartley, E.* ; Davis, H.W.* ; Zhao, Y.* ; Joseph, A.* ; Kruthaupt, T.* ; Ottaway, N.* ; Kabra, D.G. ; Habegger, K.M.* ; Benoit, S.C.* ; Bidlingmaier, M.* ; Thorner, M.O.* ; Perez-Tilve, D.* ; Tschöp, M.H. ; Pfluger, P.T.

The GOAT-ghrelin system is not essential for hypoglycemia prevention during prolonged calorie restriction.

PLoS ONE 7:e32100 (2012)

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Ghrelin 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. METHODOLOGY: Male 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 FINDINGS: Chronic 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. CONCLUSION: The endogenous GOAT-ghrelin-GHSR system is not essential for the maintenance of euglycemia during prolonged calorie restriction.

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