title: Metabolic Benefit of Chronic Caloric Restriction and Activation of Hypothalamic AGRP/NPY Neurons in Male Mice Is Independent of Ghrelin.
abstract: Aging is associated with attenuated ghrelin signaling. During aging, chronic caloric restriction (CR) produces health benefits accompanied by enhanced ghrelin production. Ghrelin receptor (GH secretagogue receptor 1a) agonists administered to aging rodents and humans restore the young adult phenotype; therefore, we tested the hypothesis that the metabolic benefits of CR are mediated by endogenous ghrelin. Three month-old male mice lacking ghrelin (Ghrelin-/-) or ghrelin receptor (Ghsr-/-), and their wild-type (WT) littermates were randomly assigned to 2 groups: ad libitum (AL) fed and CR, where 40% food restriction was introduced gradually to allow Ghrelin-/- and Ghsr-/- mice to metabolically adapt and avoid severe hypoglycemia. Twelve months later, plasma ghrelin, metabolic parameters, ambulatory activity, hypothalamic and liver gene expression, as well as body composition were measured. CR increased plasma ghrelin and des-acyl ghrelin concentrations in WT and Ghsr-/- mice. CR of WT, Ghsr-/-, and Ghrelin-/- mice markedly improved metabolic flexibility, enhanced ambulatory activity, and reduced adiposity. Inactivation of Ghrelin or Ghsr had no effect on AL food intake or food anticipatory behavior. In contrast to the widely held belief that endogenous ghrelin regulates food intake, CR increased expression of hypothalamic Agrp and Npy, with reduced expression of Pomc across genotypes. In the AL context, ablation of ghrelin signaling markedly inhibited liver steatosis, which correlated with reduced Pparγ expression and enhanced Irs2 expression. Although CR and administration of GH secretagogue receptor 1a agonists both benefit the aging phenotype, we conclude the benefits of chronic CR are a consequence of enhanced metabolic flexibility independent of endogenous ghrelin or des-acyl ghrelin signaling.
authors.affiliation: Department of Metabolism and Aging (N.H.R., H.W., O.A.-G., S.P., R.G.S.), The Scripps Research Institute Florida, Jupiter, Florida 33458; and Division of Endocrinology and Metabolism (B.G., M.O.T.), Department of Medicine, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Rogers
authors.affiliation: Department of Metabolism and Aging (N.H.R., H.W., O.A.-G., S.P., R.G.S.), The Scripps Research Institute Florida, Jupiter, Florida 33458; and Division of Endocrinology and Metabolism (B.G., M.O.T.), Department of Medicine, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Heidi
authors.initials: H
authors.lastname: Walsh
authors.affiliation: Department of Metabolism and Aging (N.H.R., H.W., O.A.-G., S.P., R.G.S.), The Scripps Research Institute Florida, Jupiter, Florida 33458; and Division of Endocrinology and Metabolism (B.G., M.O.T.), Department of Medicine, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Oscar
authors.initials: O
authors.lastname: Alvarez-Garcia
authors.affiliation: Department of Metabolism and Aging (N.H.R., H.W., O.A.-G., S.P., R.G.S.), The Scripps Research Institute Florida, Jupiter, Florida 33458; and Division of Endocrinology and Metabolism (B.G., M.O.T.), Department of Medicine, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Seongjoon
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Metabolism and Aging (N.H.R., H.W., O.A.-G., S.P., R.G.S.), The Scripps Research Institute Florida, Jupiter, Florida 33458; and Division of Endocrinology and Metabolism (B.G., M.O.T.), Department of Medicine, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Bruce
authors.initials: B
authors.lastname: Gaylinn
authors.affiliation: Department of Metabolism and Aging (N.H.R., H.W., O.A.-G., S.P., R.G.S.), The Scripps Research Institute Florida, Jupiter, Florida 33458; and Division of Endocrinology and Metabolism (B.G., M.O.T.), Department of Medicine, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Thorner
authors.affiliation: Department of Metabolism and Aging (N.H.R., H.W., O.A.-G., S.P., R.G.S.), The Scripps Research Institute Florida, Jupiter, Florida 33458; and Division of Endocrinology and Metabolism (B.G., M.O.T.), Department of Medicine, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Roy G
authors.initials: RG
authors.lastname: Smith
mesh_terms: D000367:Age Factors; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001823:Body Composition / Q000235:genetics; D031204:Caloric Restriction; D004435:Eating / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D015870:Gene Expression; D054439:Ghrelin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D054440:Receptors, Ghrelin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D054439:Ghrelin; D009478:Neuropeptide Y; D054440:Receptors, Ghrelin
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