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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Available from: Gwen V Childs
    • "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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    ABSTRACT: Leptin is an adipocyte-derived hormone that not only regulates food intake and energy homeostasis but also induces growth hormone (GH) mRNA expression and release, thereby controlling growth and metabolism in mammals. The molecular mechanism of leptin-induced regulation of GH gene transcription is unclear. The current study investigated the effects of leptin on the chicken GH (cGH) promoter and the molecular mechanism underlying leptin-induced cGH gene expression in vitro. Leptin activated the cGH promoter in the presence of chPit-1α in CHO cells stably expressing the chicken leptin receptor. Promoter activation did not require STAT-binding elements in the cGH promoter or STAT3 activity. However, JAK2 activation was required for leptin-dependent activity. JAK2-dependent pathways include p42/44 MAPK and PI3K, and inhibition of these pathways partially blocked leptin-induced cGH gene transcription. Although CK2 directly activates JAK2, a CK2 inhibitor blocked leptin-dependent activation of the cGH gene without affecting JAK2 phosphorylation. The CK2 inhibitor suppressed Erk1/2 and Akt phosphorylation. Additional data implicate Src family kinases in leptin-dependent cGH gene activation. These results suggest that leptin activates the GH gene in the presence of chPit-1α via several leptin-activated kinases. Although further study is required, we suggest that the leptin-induced JAK2/p42/44 MAPK and JAK2/PI3K cascades are activated by Src-meditated CK2, leading to CBP phosphorylation and interaction with chPit-1α, resulting in transactivation of the cGH promoter.
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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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    ABSTRACT: Decreased growth hormone (GH) function in obese patients might contribute to associated metabolic abnormalities. This study aimed to in-vestigate the effect of leptin, GH and periods of leptin sensitivity or/and insensitivity on the ex-pression of the SOCS-3 gene in the ovine pi-tuitary and to examine the influence of centrally administered leptin on GH release in sheep. Our first experiment investigated the periods of leptin resistance and leptin sensitivity, which are known as the long day (LD) and the short day (SD) periods, respectively, using ewes that were surgically fitted with third ventricular cannulae. The ewes were assigned randomly to one of three treatments and were centrally infused at 0, 1 and 2 h, beginning at sunset. The treatments consisted of central infusions of either Ringer-Locke buffer or leptin (0.5 or 1.0 μg/kg body weight (BW), respectively). Our next experiment examined the pituitaries isolated from ewes de-capitated in either May or November. The ex-plants were treated with control or GH (100 or 300 ng/ml) or leptin (50 or 100 ng/ml)—containing media and incubated for one of four different time intervals. The in vivo experiments demon-strated variable effects of leptin on GH release depending on the period of leptin sensitivity/ insensitivity. The in vitro experiments demon-strated that leptin significantly influenced the expression of the SOCS-3 gene during that SD compared to during the LD. During the SD, we observed that significantly low or high doses of GH affected the expression of SOCS-3. These results indicated a strong correlation between leptin or GH and SOCS-3, which might explain leptin resistance and the associated perturba-tions in GH signaling.
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    ABSTRACT: Circulating growth hormone (GH) levels rise in response to nutrient deprivation and fall in states of nutrient excess. Because GH regulates carbohydrate, lipid, and protein metabolism, defining the mechanisms by which changes in metabolism alter GH secretion will aid in our understanding of the cause, progression, and treatment of metabolic diseases. This review will summarize what is currently known regarding the impact of systemic metabolic signals on GH-axis function. In addition, ongoing studies using the Cre/loxP system to generate mouse models with selective somatotrope resistance to metabolic signals will be discussed, where these models will serve to enhance our understanding of the specific role the somatotrope plays in sensing the metabolic environment and adjusting GH output in metabolic extremes.
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