title: The somatotrope as a metabolic sensor: deletion of leptin receptors causes obesity.
abstract: Leptin, the product of the Lep gene, reports levels of adiposity to the hypothalamus and other regulatory cells, including pituitary somatotropes, which secrete GH. Leptin deficiency is associated with a decline in somatotrope numbers and function, suggesting that leptin may be important in their maintenance. This hypothesis was tested in a new animal model in which exon 17 of the leptin receptor (Lepr) protein was selectively deleted in somatotropes by Cre-loxP technology. Organ genotyping confirmed the recombination of the floxed LepR allele only in the pituitary. Deletion mutant mice showed a 72% reduction in pituitary cells bearing leptin receptor (LEPR)-b, a 43% reduction in LEPR proteins and a 60% reduction in percentages of immunopositive GH cells, which correlated with reduced serum GH. In mutants, LEPR expression by other pituitary cells was like that of normal animals. Leptin stimulated phosphorylated Signal transducer and activator of transcription 3 expression in somatotropes from normal animals but not from mutants. Pituitary weights, cell numbers, IGF-I, and the timing of puberty were not different from control values. Growth curves were normal during the first 3 months. Deletion mutant mice became approximately 30-46% heavier than controls with age, which was attributed to an increase in fat mass. Serum leptin levels were either normal in younger animals or reflected the level of obesity in older animals. The specific ablation of the Lepr exon 17 gene in somatotropes resulted in GH deficiency with a consequential reduction in lipolytic activity normally maintained by GH and increased adiposity.
authors.affiliation: Professor and Chair, Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. childsgwenv@uams.edu
authors.forename: Gwen V
authors.initials: GV
authors.lastname: Childs
authors.forename: Noor
authors.initials: N
authors.lastname: Akhter
authors.forename: Anessa
authors.initials: A
authors.lastname: Haney
authors.forename: Mohsin
authors.initials: M
authors.lastname: Syed
authors.forename: Angela
authors.initials: A
authors.lastname: Odle
authors.forename: Michael
authors.initials: M
authors.lastname: Cozart
authors.forename: Zachary
authors.initials: Z
authors.lastname: Brodrick
authors.forename: Dana
authors.initials: D
authors.lastname: Gaddy
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Suva
authors.forename: Nisreen
authors.initials: N
authors.lastname: Akel
authors.forename: Christopher
authors.initials: C
authors.lastname: Crane
authors.forename: Helen
authors.initials: H
authors.lastname: Benes
authors.forename: Amanda
authors.initials: A
authors.lastname: Charlesworth
authors.forename: Raul
authors.initials: R
authors.lastname: Luque
authors.forename: Streamson
authors.initials: S
authors.lastname: Chua
authors.forename: Rhonda D
authors.initials: RD
authors.lastname: Kineman
mesh_terms: D015502:Absorptiometry, Photon; D000483:Alleles; D000818:Animals; D001823:Body Composition; D004734:Energy Metabolism / Q000235:genetics* / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D007328:Insulin / Q000097:blood; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010907:Pituitary Hormones / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics* / Q000378:metabolism*; D015430:Weight Gain
chemical_list: D007328:Insulin; D020738:Leptin; D010907:Pituitary Hormones; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; C045073:Cre recombinase; D019426:Integrases