title: The GOAT-ghrelin system is not essential for hypoglycemia prevention during prolonged calorie restriction.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  The endogenous GOAT-ghrelin-GHSR system is not essential for the maintenance of euglycemia during prolonged calorie restriction.
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Centre Munich, Neuherberg, Germany.
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Yi
authors.forename: Kristy M
authors.initials: KM
authors.lastname: Heppner
authors.forename: Henriette
authors.initials: H
authors.lastname: Kirchner
authors.forename: Jenny
authors.initials: J
authors.lastname: Tong
authors.forename: Maximillian
authors.initials: M
authors.lastname: Bielohuby
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gaylinn
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.forename: Erin
authors.initials: E
authors.lastname: Bartley
authors.forename: Harold W
authors.initials: HW
authors.lastname: Davis
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Anupama
authors.initials: A
authors.lastname: Joseph
authors.forename: Traci
authors.initials: T
authors.lastname: Kruthaupt
authors.forename: Nickki
authors.initials: N
authors.lastname: Ottaway
authors.forename: Dhiraj
authors.initials: D
authors.lastname: Kabra
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Habegger
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Benoit
authors.forename: Martin
authors.initials: M
authors.lastname: Bidlingmaier
authors.forename: Michael O
authors.initials: MO
authors.lastname: Thorner
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
mesh_terms: D000217:Acyltransferases / Q000378:metabolism*; D050154:Adiposity; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D031204:Caloric Restriction; D005260:Female; D005838:Genotype; D054439:Ghrelin / Q000097:blood / Q000378:metabolism*; D007003:Hypoglycemia / Q000097:blood / Q000517:prevention & control*; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal
chemical_list: D001786:Blood Glucose; D054439:Ghrelin; D007328:Insulin; D008565:Membrane Proteins; C422650:ghrelin, des-n-octanoyl; D007334:Insulin-Like Growth Factor I; D000217:Acyltransferases; C526983:Mboat4 protein, mouse