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Section of Endocrinology and Metabolism, Department of Medicine, University of Illinois at Chicago, and Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612
Address all correspondence and requests for reprints to: Dr. Rhonda D. Kineman, Jesse Brown Veterans Affairs Medical Center, Research and Development Division, M.P. 151, West Side, Suite 6215, 820 South Damen Avenue, Chicago, Illinois 60612. E-mail: kineman{at}uic.edu.
There is a negative relationship between obesity and GH. However, it is not known how metabolic changes, associated with obesity, lead to a reduction in GH output. This study examined the GH axis of two mouse models of obesity, the leptin-deficient (ob/ob) mouse and the diet-induced obese (DIO; high-fat fed) mouse. Both models displayed hyperglycemia and hyperinsulinemia with reduced expression of GH as well as reduced expression of pituitary receptors important for GH synthesis and release [GHRH receptor (DIO only) and the ghrelin receptor (ob/ob and DIO)]. These pituitary changes were not accompanied by changes in hypothalamic expression of GHRH or somatostatin; suggesting that alterations in pituitary function may be precipitated in part by direct effects of systemic signals. Of the metabolic and hormonal parameters examined (insulin, glucose, corticosterone, free fatty acids, ghrelin, and IGF-I), only insulin/glucose showed a significant, and negative, correlation with pituitary expression. Pituitaries of DIO mice remained responsive to the acute in vivo actions of insulin, as assessed by phosphorylation of Akt, despite systemic (skeletal muscle and fat) insulin resistance. In addition, treating primary pituitary cell cultures from lean mice with insulin reduced GH release as well as GH, GHRH receptor, and ghrelin receptor mRNA levels compared with vehicle-treated controls, where the magnitude of suppression of pituitary mRNA levels was similar to that observed in the DIO mouse. These results coupled with the fact that the pituitary expresses the insulin receptor at levels comparable to tissues classically considered insulin sensitive, indicates high circulating insulin levels can directly contribute to the suppression of GH synthesis and release in the obese state.
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R. M. Luque and R. D. Kineman Gender-Dependent Role of Endogenous Somatostatin in Regulating Growth Hormone-Axis Function in Mice Endocrinology, December 1, 2007; 148(12): 5998 - 6006. [Abstract] [Full Text] [PDF]
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R. M. Luque, R. D. Kineman, and M. Tena-Sempere Regulation of Hypothalamic Expression of KiSS-1 and GPR54 Genes by Metabolic Factors: Analyses Using Mouse Models and a Cell Line Endocrinology, October 1, 2007; 148(10): 4601 - 4611. [Abstract] [Full Text] [PDF]
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H. Iwakura, T. Akamizu, H. Ariyasu, T. Irako, K. Hosoda, K. Nakao, and K. Kangawa Effects of ghrelin administration on decreased growth hormone status in obese animals Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E819 - E825. [Abstract] [Full Text] [PDF]
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Z. H. Huang, R. M. Luque, R. D. Kineman, and T. Mazzone Nutritional regulation of adipose tissue apolipoprotein E expression Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E203 - E209. [Abstract] [Full Text] [PDF]
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 R. D Kineman, M. D Gahete, and R. M Luque Identification of a mouse ghrelin gene transcript that contains intron 2 and is regulated in the pituitary and hypothalamus in response to metabolic stress J. Mol. Endocrinol., May 1, 2007; 38(5): 511 - 521. [Abstract] [Full Text] [PDF]
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R. M. Luque, G. Amargo, S. Ishii, C. Lobe, R. Franks, H. Kiyokawa, and R. D. Kineman Reporter Expression, Induced by a Growth Hormone Promoter-Driven Cre Recombinase (rGHp-Cre) Transgene, Questions the Developmental Relationship between Somatotropes and Lactotropes in the Adult Mouse Pituitary Gland Endocrinology, May 1, 2007; 148(5): 1946 - 1953. [Abstract] [Full Text] [PDF]
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R. M. Luque, Z. H. Huang, B. Shah, T. Mazzone, and R. D. Kineman Effects of leptin replacement on hypothalamic-pituitary growth hormone axis function and circulating ghrelin levels in ob/ob mice Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E891 - E899. [Abstract] [Full Text] [PDF]
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R. M. Luque, S. Park, and R. D. Kineman Severity of the Catabolic Condition Differentially Modulates Hypothalamic Expression of Growth Hormone-Releasing Hormone in the Fasted Mouse: Potential Role of Neuropeptide Y and Corticotropin-Releasing Hormone Endocrinology, January 1, 2007; 148(1): 300 - 309. [Abstract] [Full Text] [PDF]
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R. M Luque, M. D Gahete, R. J Valentine, and R. D Kineman Examination of the direct effects of metabolic factors on somatotrope function in a non-human primate model, Papio anubis. J. Mol. Endocrinol., August 1, 2006; 37(1): 25 - 38. [Abstract] [Full Text] [PDF]
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