The somatotrope as a metabolic sensor: deletion of leptin receptors causes obesity.
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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.
author list (cited authors)
Childs, G. V., Akhter, N., Haney, A., Syed, M., Odle, A., Cozart, M., ... Kineman, R. D.
complete list of authors
Childs, Gwen V||Akhter, Noor||Haney, Anessa||Syed, Mohsin||Odle, Angela||Cozart, Michael||Brodrick, Zachary||Gaddy, Dana||Suva, Larry J||Akel, Nisreen||Crane, Christopher||Benes, Helen||Charlesworth, Amanda||Luque, Raul||Chua, Streamson||Kineman, Rhonda D