Growth hormone (GH) promotes protein synthesis and lipolysis. In turn, metabolic disturbances are associated with alteration in GH production which contribute to the pathophysiology of clinically relevant disorders such as malnutrition, anorexia nervosa, obesity and diabetes. Despite the strong association between metabolism and GH, little is known regarding the basic mechanisms by which perturbations in metabolic pathways bring about changes in GH synthesis and release. Therefore, this application will determine the mechanisms by which alterations in nutrient availability; 1) regulate hypothalamic expression of neuropeptides essential for normal pituitary GH production (GH-releasing hormone [GHRH] and somatostatin [SRIF]), and 2) modify pituitary sensitivity to the GH-stimulatory peptides, GHRH and ghrelin. It has been proposed that changes in circulating leptin (an adipocyte factor) and ghrelin (a GH-releasing peptide produced in the stomach) mediates hypothalamic expression of GHRH and SRIF through activation of neuropeptide Y (NPY) neurons. To test this hypothesis, the effects of fasting on neuropeptide mRNA levels, in mice harboring defects in leptin synthesis (ob/ob), tissue source of leptin (AZIP-F1), NPY synthesis (NPY-/-), SRIF synthesis (smst-/-) and SRIF signaling (ss1l/2-/-) will be examined by ribonuclease protection assay and in situ hybridization. Also the effects of fasting in normal mice following exogenous hormone replacement (to increase NPY, leptin or ghrelin), pharmacological treatment (to block endogenous NPY production) or passive immunoneutralization (to block the actions of ghrelin) will be tested. Fasting not only alters expression of GH-regulatory neuropeptides but also enhances pituitary sensitivity to GHRH and ghrelin by increasing GHRH-R and GHS-R mRNA levels. In vitro, FFAs alone or in conjunction with glucocorticoids increase GHS-R synthesis. Therefore it is hypothesized that fasting induced elevations in FFA and glucocorticoids are required to enhance pituitary receptor synthesis and sensitivity, and thus compensate for fasting-induced alteration in central signals. To test this hypothesis, studies will examine the ability of fasting to alter pituitary receptor expression (by quantitative RT-PCR) and dynamic GH release (by RIA of serial blood samples) following blockade of FFA formation (by the anti-lipolytic Acipimox) or glucocorticoid actions (by the glucocorticoid receptor antagonist, RU-486). Also primary rat and non-human primate (baboon) pituitary call cultures will be used to determine if FFA and glucocorticoids mediate their effects on receptor synthesis via transcriptional or post-transcriptional processes and if the effects of FFA can be mimicked by activation of the putative FFA nuclear receptors, peroxisome proliferator-activated receptors (PPAR). This is the second revision of a competitive renewal of an RO1 application which continues to study the regulation of the GH axis. The current application centers on the interrelationship between changes in metabolic function and the GH axis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Endocrinology Study Section (END)
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Malozowski, Saul N
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University of Illinois at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Luque, Raul M; Gahete, Manuel D; Cordoba-Chacon, Jose et al. (2011) Does the pituitary somatotrope play a primary role in regulating GH output in metabolic extremes? Ann N Y Acad Sci 1220:82-92
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Cordoba-Chacon, Jose; Gahete, Manuel D; Duran-Prado, Mario et al. (2010) Identification and characterization of new functional truncated variants of somatostatin receptor subtype 5 in rodents. Cell Mol Life Sci 67:1147-63
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Sandoval, Raudel; Xue, Jiaping; Tian, Xinyong et al. (2006) A mutant allele of BARA/LIN-9 rescues the cdk4-/- phenotype by releasing the repression on E2F-regulated genes. Exp Cell Res 312:2465-75
Luque, Raul M; Duran-Prado, Mario; Garcia-Navarro, Socorro et al. (2006) Identification of the somatostatin receptor subtypes (sst) mediating the divergent, stimulatory/inhibitory actions of somatostatin on growth hormone secretion. Endocrinology 147:2902-8
Park, Seungjoon; Sohn, Sookjin; Kineman, Rhonda D (2004) Fasting-induced changes in the hypothalamic-pituitary-GH axis in the absence of GH expression: lessons from the spontaneous dwarf rat. J Endocrinol 180:369-78

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