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Growth hormone insensitivity and obesity: Insights from human and animal models
Obesity Research & Clinical Practice (2009) 3, 1—2
EDITORIAL
Growth hormone insensitivity and obesity: Insights from human and animal models In this issue the paper entitled ‘The obesity of patients with Laron Syndrome is not associate with excessive nutritional intake’ by Ginsburg and colleagues, is of interest. Laron is credited with identifying and describing the syndrome of GH insensitivity syndrome. Thus the question should be raised about the phenotype of animals with either GH deficiency or GH receptor knock out [1]. Both have been described and do not diverge from the description of the subjects in this report. Donahue and Beamer described the impact of GH deficiency in the lit/lit mouse [2]. This is due to an inactivating point mutation in the growth hormone releasing hormone receptor [3]. These animals have reduced IGF-I levels and have increased fat mass and reduced body water, protein and mineral from 2 weeks of age on. Interestingly they documented that these animals had normal energy intake up to 52 weeks of age indicating that neither undernutrition nor hyperphagia were responsible. Thus the phenotype and the nutritional intake is well documented in the mouse model. More recently we have demonstrated that growth hormone regulates p85␣ mRNA and protein expression in white adipose tissue of mice with growth hormone excess, deficiency and sufficiency [4]. The deficiency models included GH-R knockout and the lit/lit mouse. We found that GH regulates p85␣ expression and PI 3-kinase activity in white adipose tissue. GH deficiency is associated with decreased p85a expression and improved PI3 kinase activity and provides an explanation for the insulin hypersensitivity and associated obesity and hyperadiponectinemia of GH-deficient mice; the corollary is the insulin resistance and
associated reduced fat mass and hypoadiponectinemia of mice with GH excess due to enhanced p85␣ expression and reduced PI3 kinase activity. In summary, the observations made by Ginsburg and colleagues in patients with Laron Syndrome are the result of absent GH signaling secondary to a mutation in the GH receptor. The phenotype and nutritional intake is similar to that described in the lit/lit mouse and the likely explanation for this is that the fat tissue is supersensitive to insulin due to lack of GH signaling. Growth hormone is recognized as an important partitioning hormone and this study further documents its important role.
References [1] Berryman DE, List EO, Coschigano KT, Behar K, Kim JK, Kopchich JJ. Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Horm IGF Res 2004;14:309—18. [2] Donahue LR, Beamer WG. Growth hormone deficiency in ‘little’ mice results in aberrant body composition, reduced insulin-like growth factor-I and insulin-like growth factorbinding protein-3 (IGFBP-3), but does not affect IGFBP-2 -1 or -4. J Endocrinol 1993;136:91—104. [3] Godfrey P, Rahal JO, Beamer WG, Copeland NG, Jenkins NA, Mayo KE. GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat Genet 1993;4:227—32. [4] del Rincon JP, Iida K, Gaylinn BD, McCurdy CE, Leitner JW, Barbour LA, et al. Growth hormone regulation of p85 alpha expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance. Diabetes 2007;56: 1638—46.
1871-403X/$ — see front matter © 2009 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.orcp.2009.01.002
2
Editorial Michael O. Thorner University of Virginia Health System, Endocrinology and Metabolism, Box 801411
Charlottesville, VA 22908, United States E-mail address: [email protected]
Available online at www.sciencedirect.com
EDITORIAL
Growth hormone insensitivity and obesity: Insights from human and animal models In this issue the paper entitled ‘The obesity of patients with Laron Syndrome is not associate with excessive nutritional intake’ by Ginsburg and colleagues, is of interest. Laron is credited with identifying and describing the syndrome of GH insensitivity syndrome. Thus the question should be raised about the phenotype of animals with either GH deficiency or GH receptor knock out [1]. Both have been described and do not diverge from the description of the subjects in this report. Donahue and Beamer described the impact of GH deficiency in the lit/lit mouse [2]. This is due to an inactivating point mutation in the growth hormone releasing hormone receptor [3]. These animals have reduced IGF-I levels and have increased fat mass and reduced body water, protein and mineral from 2 weeks of age on. Interestingly they documented that these animals had normal energy intake up to 52 weeks of age indicating that neither undernutrition nor hyperphagia were responsible. Thus the phenotype and the nutritional intake is well documented in the mouse model. More recently we have demonstrated that growth hormone regulates p85␣ mRNA and protein expression in white adipose tissue of mice with growth hormone excess, deficiency and sufficiency [4]. The deficiency models included GH-R knockout and the lit/lit mouse. We found that GH regulates p85␣ expression and PI 3-kinase activity in white adipose tissue. GH deficiency is associated with decreased p85a expression and improved PI3 kinase activity and provides an explanation for the insulin hypersensitivity and associated obesity and hyperadiponectinemia of GH-deficient mice; the corollary is the insulin resistance and
associated reduced fat mass and hypoadiponectinemia of mice with GH excess due to enhanced p85␣ expression and reduced PI3 kinase activity. In summary, the observations made by Ginsburg and colleagues in patients with Laron Syndrome are the result of absent GH signaling secondary to a mutation in the GH receptor. The phenotype and nutritional intake is similar to that described in the lit/lit mouse and the likely explanation for this is that the fat tissue is supersensitive to insulin due to lack of GH signaling. Growth hormone is recognized as an important partitioning hormone and this study further documents its important role.
References [1] Berryman DE, List EO, Coschigano KT, Behar K, Kim JK, Kopchich JJ. Comparing adiposity profiles in three mouse models with altered GH signaling. Growth Horm IGF Res 2004;14:309—18. [2] Donahue LR, Beamer WG. Growth hormone deficiency in ‘little’ mice results in aberrant body composition, reduced insulin-like growth factor-I and insulin-like growth factorbinding protein-3 (IGFBP-3), but does not affect IGFBP-2 -1 or -4. J Endocrinol 1993;136:91—104. [3] Godfrey P, Rahal JO, Beamer WG, Copeland NG, Jenkins NA, Mayo KE. GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat Genet 1993;4:227—32. [4] del Rincon JP, Iida K, Gaylinn BD, McCurdy CE, Leitner JW, Barbour LA, et al. Growth hormone regulation of p85 alpha expression and phosphoinositide 3-kinase activity in adipose tissue: mechanism for growth hormone-mediated insulin resistance. Diabetes 2007;56: 1638—46.
1871-403X/$ — see front matter © 2009 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.orcp.2009.01.002
2
Editorial Michael O. Thorner University of Virginia Health System, Endocrinology and Metabolism, Box 801411
Charlottesville, VA 22908, United States E-mail address: [email protected]
Available online at www.sciencedirect.com