Hormonal Regulation of Growth and Metabolic Effects of Growth Hormone

Kaplan, Selna L.

doi:10.1002/cphy.cp070505

Cited by 20 publications

(19 citation statements)

References 170 publications

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“…Children and adults with growth hormone deficiency exhibit fasting hypoglycemia (decreased hepatic production of glucose), increased insulin sensitivity, and diminished insulin secretion (22). Rodent models of chronic growth hormone excess are useful tools to investigate the mechanism by which growth hormone induces insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice

Liu¹,

Coschigano²,

Robertson³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

204

151

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Growth hormone, acting through its receptor (GHR), plays an important role in carbohydrate metabolism and in promoting postnatal growth. GHR gene-deficient (GHR(-/-)) mice exhibit severe growth retardation and proportionate dwarfism. To assess the physiological relevance of growth hormone actions, GHR(-/-) mice were used to investigate their phenotype in glucose metabolism and pancreatic islet function. Adult GHR(-/-) mice exhibited significant reductions in the levels of blood glucose and insulin, as well as insulin mRNA accumulation. Immunohistochemical analysis of pancreatic sections revealed normal distribution of the islets despite a significantly smaller size. The average size of the islets found in GHR(-/-) mice was only one-third of that in wild-type littermates. Total beta-cell mass was reduced 4.5-fold in GHR(-/-) mice, significantly more than their body size reduction. This reduction in pancreatic islet mass appears to be related to decreases in proliferation and cell growth. GHR(-/-) mice were different from the human Laron syndrome in serum insulin level, insulin responsiveness, and obesity. We conclude that growth hormone signaling is essential for maintaining pancreatic islet size, stimulating islet hormone production, and maintaining normal insulin sensitivity and glucose homeostasis.

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Section: Discussionmentioning

confidence: 99%

Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice

Liu¹,

Coschigano²,

Robertson³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

204

151

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“…GH exerts growth-promoting and metabolic effects in target tissues (11) by binding to the transmembrane GHR and triggering enhanced GHR association with, and activation of, the cytoplasmic tyrosine kinase JAK2 (12,13). Three major signaling systems activated in response to GH include STATs (most notably STAT5b), phosphoinositide 3-kinase (PI3K), and Erk (14,15).…”

Section: Introductionmentioning

confidence: 99%

Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice

Mavalli¹,

DiGirolamo²,

Fan³

et al. 2010

J. Clin. Invest.

180

138

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Skeletal muscle development, nutrient uptake, and nutrient utilization is largely coordinated by growth hormone (GH) and its downstream effectors, in particular, IGF-1. However, it is not clear which effects of GH on skeletal muscle are direct and which are secondary to GH-induced IGF-1 expression. Thus, we generated mice lacking either GH receptor (GHR) or IGF-1 receptor (IGF-1R) specifically in skeletal muscle. Both exhibited impaired skeletal muscle development characterized by reductions in myofiber number and area as well as accompanying deficiencies in functional performance. Defective skeletal muscle development, in both GHR and IGF-1R mutants, was attributable to diminished myoblast fusion and associated with compromised nuclear factor of activated T cells import and activity. Strikingly, mice lacking GHR developed metabolic features that were not observed in the IGF-1R mutants, including marked peripheral adiposity, insulin resistance, and glucose intolerance. Insulin resistance in GHR-deficient myotubes derived from reduced IR protein abundance and increased inhibitory phosphorylation of IRS-1 on Ser 1101. These results identify distinct signaling pathways through which GHR regulates skeletal muscle development and modulates nutrient metabolism. IntroductionMammalian skeletal muscle has evolved to perform a diverse set of functions, including locomotion, breathing, protecting internal organs, and coordinating global energy expenditure. Skeletal muscle is formed and regenerated through a highly regulated process characterized by myoblast differentiation and fusion into multinucleated syncytia. During embryonic development, specification of mesodermal precursor cells into the myogenic lineage is controlled by signals from surrounding tissues and requires upregulation of several factors, including paired-box transcription factor 7 (pax-7) and basic helix-loop-helix transcriptional activators of the myogenic regulatory factor family, MyoD and Myf-5 (1). The proliferating precursor cells/myoblasts withdraw from the cell cycle and initiate muscle-specific gene expression (2, 3). Myoblasts then initially fuse to form nascent myotubes, with relatively few nuclei, through a highly ordered set of cellular events, including recognition, adhesion, alignment, and membrane union. Subsequent recruitment and fusion of additional myoblasts gives rise to multinucleated myotubes that ultimately mature to give rise to skeletal muscle fibers. The fusion process is controlled, in part, by the actions of calcium-sensitive transcription factors of the nuclear factor of activated T cells (NFAT) family (4, 5). During myoblast fusion,

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“…Pituitary Growth Hormone (GH) has long been known as a major regulator of normal growth and metabolism (1)(2)(3). Among its diverse actions, GH promotes statural growth in conjunction with Insulin-like Growth Factor 1 (IGF-1) by stimulating chondrocytes in long bones (4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Multiple mechanisms of growth hormone-regulated gene transcription

Ceseña

Cui

Piwien-Pilipuk³

et al. 2007

Molecular Genetics and Metabolism

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Diverse physiological actions of growth hormone (GH) are mediated by changes in gene transcription. Transcription can be regulated at several levels, including post-translational modification of transcription factors, and formation of multiprotein complexes involving transcription factors, co-regulators and additional nuclear proteins; these serve as targets for regulation by hormones and signaling pathways. Evidence that GH regulates transcription at multiple levels is exemplified by analysis of the proto-oncogene c-fos. Among the GH-regulated transcription factors on c-fos, C/EBPβ appears to be key, since depletion of C/EBPβ by RNA interference blocks the stimulation of c-fos by GH. The phosphorylation state of C/EBPβ and its ability to activate transcription are regulated by GH through MAPK and PI3K/Akt-mediated signaling cascades. The acetylation of C/EBPβ also contributes to its ability to activate c-fos transcription. These and other post-translational modifications of C/EBPβ appear to be integrated for regulation of transcription by GH. The formation of nuclear proteins into complexes associated with DNA-bound transcription factors is also regulated by GH. Both C/EBPβ and the co-activator p300 are recruited to c-fos in response to GH, altering c-fos promoter activation. In addition, GH rapidly induces spatio-temporal relocalization of C/EBPβ within the nucleus. Thus, GH-regulated gene transcription mediated by C/ EBPβ reflects the integration of diverse mechanisms including post-translational modifications, modulation of protein complexes associated with DNA and relocalization of gene regulatory proteins. Similar integration involving other transcription factors, including Stats, appears to be a feature of regulation by GH of other gene targets.

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Hormonal Regulation of Growth and Metabolic Effects of Growth Hormone

Abstract: The sections in this article are: Effects of Growth Hormone on Body Metabolism Protein Metabolism Fat Metabolism Carbohydrate Metabolism Bone Metabolism Electrolyte and Fluid Metabolism Cardiovascular Disease Linear Gr… Show more

Cited by 20 publications

References 170 publications

Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice

Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice

Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice

Multiple mechanisms of growth hormone-regulated gene transcription

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