the ghrelin-growth hormone axis preserves gluconeogenesis to maintain blood glucose levels during...
TRANSCRIPT
POSTER PRESENTATION Open Access
The ghrelin-growth hormone axis preservesgluconeogenesis to maintain blood glucose levelsduring starvationDaniel P Sherbet*, Tongjin Zhao, Robert L Li, Michael S Brown, Joseph L Goldstein
From Metabolism, diet and diseaseWashington, DC, USA. 29-31 May 2012
BackgroundThe octanoylated peptide ghrelin stimulates growth hor-mone (GH) secretion during severe calorie restriction inmice, which preserves fasting blood sugar after body fathas been depleted. Genetic deletion of ghrelin-O-acyl-transferase (GOAT, which octanoylates ghrelin) rendersmice ghrelin-deficient and abrogates the normal rise inGH after several days of calorie restriction, resulting inprofound hypoglycemia. Administration of either ghrelinor GH to GOAT knockout mice restores the ability tomaintain fasting blood sugar levels during prolongedcalorie restriction. The mechanism of hypoglycemia inghrelin-deficient mice has not been described previously.
Materials and methods8-week-old male wild-type (WT) and GOAT knockoutmice were individually caged and fed 40% of their averagedaily food intake at 6pm daily during the period of calorierestriction. For glucose production measurements, 4 daysprior to calorie restriction each mouse was implanted witha jugular vein catheter. On day 6 of calorie restriction at 4pm, glucose production was assessed by infusing [3-3H]glucose through the catheter. Blood was obtained from cuttails during the infusion and plasma was separated by cen-trifugation and deproteinized. The supernatant was evapo-rated, resuspended in water, and radioactivity wasquantified with liquid scintillation counting.
ResultsGOAT and ghrelin knockout mice fail to show the nor-mal rise in GH when subjected to fasting after severaldays of 60% calorie restriction. Both mutant strains
become fat-depleted and develop profound hypoglyce-mia under these conditions. High fat feeding of GOATknockout mice prior to calorie-restriction doubled bodyfat percentage and delayed onset of hypoglycemia fromday 6 of calorie restriction to day 12. This was asso-ciated with a delayed decline in plasma free fatty acidsand b-hydroxybutyrate. Plasma levels of lactate and pyr-uvate in calorie-restricted GOAT knockout mice werehalf the levels of WT mice. Fasting hypoglycemia inGOAT knockout mice was associated with a glucoseproduction rate that was only 40% of the rate in WTmice. Administration of lactate, pyruvate, and alanine,which can be used as gluconeogenic precursors, restoredblood glucose in GOAT knockout mice. Administrationof octanoate, which cannot be used as a gluconeogenicprecursor, increased glucose production to the levelseen in WT mice and restored blood glucose, presum-ably by providing energy for gluconeogenesis.
ConclusionsGhrelin-mediated stimulation of GH is critical for main-taining blood glucose in fasting mice when fat storeshave been depleted. GH maintains plasma gluconeo-genic precursors and preserves glucose production whenendogenous (fat) and exogenous (food) fuel sources areabsent. These studies demonstrate that ghrelin and GHallow mice to maintain blood glucose during starvation.Elevated levels of both hormones are also seen instarved humans with anorexia nervosa or kwashiorkor,suggesting that the ghrelin-GH system prolongs life dur-ing starvation in both mouse and man.
Published: 1 June 2012
Department of Molecular Genetics, University of Texas Southwestern MedicalCenter, Dallas, Texas, 75390, USA
Sherbet et al. BMC Proceedings 2012, 6(Suppl 3):P65http://www.biomedcentral.com/1753-6561/6/S3/P65
© 2012 Sherbet et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
doi:10.1186/1753-6561-6-S3-P65Cite this article as: Sherbet et al.: The ghrelin-growth hormone axispreserves gluconeogenesis to maintain blood glucose levels duringstarvation. BMC Proceedings 2012 6(Suppl 3):P65.
Submit your next manuscript to BioMed Centraland take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at www.biomedcentral.com/submit
Sherbet et al. BMC Proceedings 2012, 6(Suppl 3):P65http://www.biomedcentral.com/1753-6561/6/S3/P65
Page 2 of 2