Liver-Specific gh receptor gene-Disrupted (lighrko) mice have decreased endocrine igf-I, increased local igf-I, and altered body size, body composition, and adipokine profiles

Edward O. List, Darlene E. Berryman, Kevin Funk, Adam Jara, Bruce Kelder, Feiya Wang, Michael B. Stout, Xu Zhi, Liou Sun, Thomas A. White, Nathan K LeBrasseur, Tamara Pirtskhalava, Tamara Tchkonia, Elizabeth A. Jensen, Wenjuan Zhang, Michal M. Masternak, James L Kirkland, Richard A. Miller, Andrzej Bartke, John J. Kopchick

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

GHis an important regulator of body growth and composition as well as numerous other metabolic processes. In particular, liver plays a key role in the GH/IGF-I axis, because the majority of circulating "endocrine" IGF-I results from GH-stimulated liver IGF-I production. To develop a better understanding of the role of liver in the overall function of GH, we generated a strain of mice with liver-specific GH receptor (GHR) gene knockout (LiGHRKO mice). LiGHRKO mice had a 90% decrease in circulating IGF-I levels, a 300% increase in circulating GH, and significant changes in IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, IGFBP-5,andIGFBP-7.LiGHRKOmiceweresmaller than controls, with body length and body weight being significantly decreased in both sexes. Analysis of body composition over time revealed a pattern similar to those found inGHtransgenic mice; that is, LiGHRKO mice had a higher percentage of body fat at early ages followed by lower percentage of body fat in adulthood. Local IGF-ImRNAlevels were significantly increased in skeletal muscleand select adipose tissue depots. Grip strengthwasincreased inLiGHRKOmice. Finally, circulating levels of leptin, resistin, and adiponectin were increased in LiGHRKO mice. In conclusion, LiGHRKO mice are smaller despite increased local mRNA expression of IGF-I in several tissues, suggesting that liver-derived IGF-I is indeed important for normal body growth. Furthermore, our data suggest that novel GH-dependent cross talk between liver and adipose is important for regulation of adipokines in vivo.

Original languageEnglish (US)
Pages (from-to)1793-1805
Number of pages13
JournalEndocrinology
Volume155
Issue number5
DOIs
StatePublished - 2014

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Adipokines
Body Size
Body Composition
Insulin-Like Growth Factor I
Liver
Genes
Adipose Tissue
Insulin-Like Growth Factor Binding Protein 5
Insulin-Like Growth Factor Binding Protein 2
Resistin
Insulin-Like Growth Factor Binding Protein 1
Gene Knockout Techniques
Insulin-Like Growth Factor Binding Protein 3
Adiponectin
Hand Strength
Growth
Leptin
Knockout Mice
Body Weight
Messenger RNA

ASJC Scopus subject areas

  • Endocrinology

Cite this

Liver-Specific gh receptor gene-Disrupted (lighrko) mice have decreased endocrine igf-I, increased local igf-I, and altered body size, body composition, and adipokine profiles. / List, Edward O.; Berryman, Darlene E.; Funk, Kevin; Jara, Adam; Kelder, Bruce; Wang, Feiya; Stout, Michael B.; Zhi, Xu; Sun, Liou; White, Thomas A.; LeBrasseur, Nathan K; Pirtskhalava, Tamara; Tchkonia, Tamara; Jensen, Elizabeth A.; Zhang, Wenjuan; Masternak, Michal M.; Kirkland, James L; Miller, Richard A.; Bartke, Andrzej; Kopchick, John J.

In: Endocrinology, Vol. 155, No. 5, 2014, p. 1793-1805.

Research output: Contribution to journalArticle

List, EO, Berryman, DE, Funk, K, Jara, A, Kelder, B, Wang, F, Stout, MB, Zhi, X, Sun, L, White, TA, LeBrasseur, NK, Pirtskhalava, T, Tchkonia, T, Jensen, EA, Zhang, W, Masternak, MM, Kirkland, JL, Miller, RA, Bartke, A & Kopchick, JJ 2014, 'Liver-Specific gh receptor gene-Disrupted (lighrko) mice have decreased endocrine igf-I, increased local igf-I, and altered body size, body composition, and adipokine profiles', Endocrinology, vol. 155, no. 5, pp. 1793-1805. https://doi.org/10.1210/en.2013-2086
List, Edward O. ; Berryman, Darlene E. ; Funk, Kevin ; Jara, Adam ; Kelder, Bruce ; Wang, Feiya ; Stout, Michael B. ; Zhi, Xu ; Sun, Liou ; White, Thomas A. ; LeBrasseur, Nathan K ; Pirtskhalava, Tamara ; Tchkonia, Tamara ; Jensen, Elizabeth A. ; Zhang, Wenjuan ; Masternak, Michal M. ; Kirkland, James L ; Miller, Richard A. ; Bartke, Andrzej ; Kopchick, John J. / Liver-Specific gh receptor gene-Disrupted (lighrko) mice have decreased endocrine igf-I, increased local igf-I, and altered body size, body composition, and adipokine profiles. In: Endocrinology. 2014 ; Vol. 155, No. 5. pp. 1793-1805.
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AU - List, Edward O.

AU - Berryman, Darlene E.

AU - Funk, Kevin

AU - Jara, Adam

AU - Kelder, Bruce

AU - Wang, Feiya

AU - Stout, Michael B.

AU - Zhi, Xu

AU - Sun, Liou

AU - White, Thomas A.

AU - LeBrasseur, Nathan K

AU - Pirtskhalava, Tamara

AU - Tchkonia, Tamara

AU - Jensen, Elizabeth A.

AU - Zhang, Wenjuan

AU - Masternak, Michal M.

AU - Kirkland, James L

AU - Miller, Richard A.

AU - Bartke, Andrzej

AU - Kopchick, John J.

PY - 2014

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N2 - GHis an important regulator of body growth and composition as well as numerous other metabolic processes. In particular, liver plays a key role in the GH/IGF-I axis, because the majority of circulating "endocrine" IGF-I results from GH-stimulated liver IGF-I production. To develop a better understanding of the role of liver in the overall function of GH, we generated a strain of mice with liver-specific GH receptor (GHR) gene knockout (LiGHRKO mice). LiGHRKO mice had a 90% decrease in circulating IGF-I levels, a 300% increase in circulating GH, and significant changes in IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, IGFBP-5,andIGFBP-7.LiGHRKOmiceweresmaller than controls, with body length and body weight being significantly decreased in both sexes. Analysis of body composition over time revealed a pattern similar to those found inGHtransgenic mice; that is, LiGHRKO mice had a higher percentage of body fat at early ages followed by lower percentage of body fat in adulthood. Local IGF-ImRNAlevels were significantly increased in skeletal muscleand select adipose tissue depots. Grip strengthwasincreased inLiGHRKOmice. Finally, circulating levels of leptin, resistin, and adiponectin were increased in LiGHRKO mice. In conclusion, LiGHRKO mice are smaller despite increased local mRNA expression of IGF-I in several tissues, suggesting that liver-derived IGF-I is indeed important for normal body growth. Furthermore, our data suggest that novel GH-dependent cross talk between liver and adipose is important for regulation of adipokines in vivo.

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