Postreceptor Crosstalk on PI3K/Akt between GH and Insulin in Non-Catch-Up Growth Rats Born Small for Gestational Age

Huang, Ting‐Ting; Du, Mingmei; Kuluz, John W.; Li, Yanhong; Ma, Huamei

doi:10.1159/000129675

Cited by 6 publications

(6 citation statements)

References 71 publications

(50 reference statements)

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“…Studies in humans and animals have provided evidence for GH resistance in NCG-SGA [4,12,13]. In this study, we demonstrated that impairment of GH-mediated JAK2/STAT5 signal transduction is present in NCG-SGA rats.…”

Section: Discussionsupporting

confidence: 58%

Impaired Growth Hormone Receptor Signaling during Non-Catch-Up Growth in Rats Born Small for Gestational Age

Huang

Du²,

Zhuang³

et al. 2010

Horm Res Paediatr

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Background/Aims: Non-catch-up growth (NCG) in children born small for gestational age (SGA) is associated with growth hormone (GH) resistance, although the mechanisms of this association are unknown. Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling is involved in GH signal transduction. This study examined the role of JAK/STAT signaling in GH resistance of SGA rats. Methods: NCG-SGA was induced by uterine artery ligation in pregnant rats. NCG-SGA rats were treated with GH for 7 days and rats appropriate for gestational age (AGA) served as controls. Phosphorylation of JAK2/STAT5 and expression of GH receptor, suppressor of cytokine signaling 2 (SOCS-2) and cytokine-inducible SH2-containing protein (CIS) in the liver were determined by Western blotting. The expression of insulin-like growth factor 1 (IGF-1) mRNA was examined by the reverse transcription-polymerase chain reaction. Results: GH treatment significantly increased body weight and length growth rate in AGA but not in NCG-SGA rats. The increase in serum IGF-1 level and expression of IGF-1 mRNA in response to GH treatment in NCG-SGA rats was significantly less than in AGA rats. GH-induced increase in phosphorylation of JAK2/STAT5 in response to acute GH stimulation was significantly lower in NCG-SGA rats compared to AGA controls. SOCS-2 and CIS expressions significantly increased in NCG-SGA rats following GH treatment. Conclusion: GH resistance in NCG-SGA rats is associated with impaired JAK/STAT signaling and upregulated SOCS-2 and CIS expression.

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Section: Discussionsupporting

confidence: 58%

Impaired Growth Hormone Receptor Signaling during Non-Catch-Up Growth in Rats Born Small for Gestational Age

Huang

Du²,

Zhuang³

et al. 2010

Horm Res Paediatr

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“…1), yet do not show significant differences in IGF-1 expression in adulthood (data not shown). Non-catch-up growth (NCG) in children born small for gestational age (SGA) is associated with GH resistance37383940. Similar to the effect of KSR2 disruption in mouse pups (Fig.…”

Section: Discussionmentioning

confidence: 75%

Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)

Guo

Costanzo-Garvey

Smith

et al. 2016

Sci Rep

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Individuals with poor postnatal growth are at risk for cardiovascular and metabolic problems as adults. Here we show that disruption of the molecular scaffold Kinase Suppressor of Ras 2 (KSR2) causes selective inhibition of hepatic GH signaling in neonatal mice with impaired expression of IGF-1 and IGFBP3. ksr2−/− mice are normal size at birth but show a marked increase in FGF21 accompanied by reduced body mass, shortened body length, and reduced bone mineral density (BMD) and content (BMC) first evident during postnatal development. However, disrupting FGF21 in ksr2−/− mice does not normalize mass, length, or bone density and content in fgf21−/−ksr2−/− mice. Body length, BMC and BMD, but not body mass, are rescued by infection of two-day-old ksr2−/− mice with a recombinant adenovirus encoding human IGF-1. Relative to wild-type mice, GH injections reveal a significant reduction in JAK2 and STAT5 phosphorylation in liver, but not in skeletal muscle, of ksr2−/− mice. However, primary hepatocytes isolated from ksr2−/− mice show no reduction in GH-stimulated STAT5 phosphorylation. These data indicate that KSR2 functions in a cell non-autonomous fashion to regulate GH-stimulated IGF-1 expression in the liver of neonatal mice, which plays a key role in the development of body length.

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“…The PI3K/Akt signaling pathway is important for the metabolic effects of insulin (Huang et al 2008) and several studies have demonstrated that impaired insulin-stimulated activation of PI3-kinase results in reduced insulin sensitivity (Nadler et al 2001;Kruszynska et al 2002). The activation of PI3K by insulin is mediated by the p85 regulatory subunit binding to tyrosine-phosphorylated insulin receptor substrate (IRS) proteins Myers et al 1992).…”

Section: Discussionmentioning

confidence: 99%

Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β

Song¹,

Wang²,

Mao³

et al. 2013

Gene

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The effect of mouse resistin on hepatic insulin resistance in vivo and in vitro, and its possible molecular mechanism were examined. Focusing on liver glycogen metabolism and gluconeogenesis, which are important parts of glucose metabolism, in primary cultures of rat hepatocytes we found that glycogen content was significantly lower (P<0.05) after treatment with recombinant murine resistin only in the presence of insulin plus glucose stimulation. Protein levels of factors in the insulin signaling pathway involved in glycogen synthesis were examined by Western blot analysis, with the only significant change observed being the level of phosphorylated (at Ser 9) glycogen synthase kinase-3β (GSK-3β) (P<0.001). No differences in the protein levels for the insulin receptor β (IRβ), insulin receptor substrates (IRS1 and IRS2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) or their phosphorylated forms were observed between control and resistin treated primary rat hepatocytes. In a mouse model with high liver-specific expression of resistin, fasting blood glucose levels and liver glycogen content changed. Fasting blood glucose levels were significantly higher (P<0.001) in the model mice, compared to the control mice, while the glycogen content of the liver tissue was about 60% of that of the control mice (P<0.05). The gluconeogenic response was not altered between the experimental and control mice. The level of phosphorylated GSK-3β in the liver tissue was also decreased (P<0.05) in the model mice, consistent with the results from the primary rat hepatocytes. Our results suggests that resistin reduces the levels of GSK-3β phosphorylated at Ser 9 leading to impaired hepatic insulin

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Postreceptor Crosstalk on PI3K/Akt between GH and Insulin in Non-Catch-Up Growth Rats Born Small for Gestational Age

Cited by 6 publications

References 71 publications

Impaired Growth Hormone Receptor Signaling during Non-Catch-Up Growth in Rats Born Small for Gestational Age

Impaired Growth Hormone Receptor Signaling during Non-Catch-Up Growth in Rats Born Small for Gestational Age

Cell non-autonomous regulation of hepatic IGF-1 and neonatal growth by Kinase Suppressor of Ras 2 (KSR2)

Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β

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