title: Mice lacking ghrelin receptors resist the development of diet-induced obesity.
abstract: Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Since its discovery, accumulating evidence has suggested that ghrelin may play a role in signaling and reversing states of energy insufficiency. For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity. However, recent loss-of-function studies have raised questions regarding the physiological significance of ghrelin in regulating these processes. Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons. We show that when fed a high-fat diet, both female and male GHSR-null mice eat less food, store less of their consumed calories, preferentially utilize fat as an energy substrate, and accumulate less body weight and adiposity than control mice. Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow. GHSR deletion also affected locomotor activity and levels of glycemia. These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control. Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity.
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Zigman
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Nakano
authors.forename: Roberto
authors.initials: R
authors.lastname: Coppari
authors.forename: Nina
authors.initials: N
authors.lastname: Balthasar
authors.forename: Jacob N
authors.initials: JN
authors.lastname: Marcus
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Lee
authors.forename: Juli E
authors.initials: JE
authors.lastname: Jones
authors.forename: Amy E
authors.initials: AE
authors.lastname: Deysher
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Waxman
authors.forename: Ryan D
authors.initials: RD
authors.lastname: White
authors.forename: Todd D
authors.initials: TD
authors.lastname: Williams
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Lachey
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000483:Alleles; D000704:Analysis of Variance; D000821:Animal Feed; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015139:Blotting, Southern; D015153:Blotting, Western; D001823:Body Composition; D001835:Body Weight; D003433:Crosses, Genetic; D004247:DNA / Q000378:metabolism; D004032:Diet; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D005838:Genotype; D054439:Ghrelin; D006579:Heterozygote; D006706:Homeostasis; D006943:Hyperglycemia / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D036361:Peptide Hormones / Q000737:chemistry / Q000502:physiology*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000502:physiology*; D054440:Receptors, Ghrelin; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D015398:Signal Transduction; D016622:Silver Staining; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D054439:Ghrelin; D020738:Leptin; D036361:Peptide Hormones; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D004247:DNA