The Somatotrope as a Metabolic Sensor: Deletion of Leptin Receptors Causes Obesity

Section of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois, United States
Endocrinology (Impact Factor: 4.5). 11/2010; 152(1):69-81. DOI: 10.1210/en.2010-0498
Source: PubMed


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.

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    • "The paracrine/autocrine system is involved in leptininduced GH function, because leptin and its receptor are expressed in somatotrophs (Iqbal et al., 2000; Jin et al., 2000; Vidal et al., 2000; Ogasawara et al, 2008). In addition, somatotroph-specific LEPR knockout mice have lower plasma GH levels and increased fat mass, clearly indicating the importance of leptin in GH release and its subsequent actions (Childs et al., 2011). Furthermore, leptin upregulates GH gene expression in pig pituitary cells (Baratta et al., 2002) and bovine pituitary explants (Accorsi et al., 2007). "
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    • "The results of that study supported the contribution of hyperleptinemia as negatively connected with GH secretion. The selective deletion of leptin receptors from somatotropic cells in mice did not affect the total cell number of the somatotroph, although there were the reduced number of GH-expressing cells and consequently GH secretion, suggesting that leptin affects GH expression and secretion but not somatotroph development [30]. A study by Luque and Kineman [31] supported the idea that a pituitary defect is a key component in the GH deficiency observed during obese states. "
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