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

Huang, Yuefang; Du, Mingmei; Zhuang, Shihao; Shen, Zhenyu; Li, Yijuan

doi:10.1159/000313374

Cited by 11 publications

(11 citation statements)

References 70 publications

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“…Similar to the effect of KSR2 disruption in mouse pups (Fig. 4), uterine artery ligation in pregnant rats to induce NCG-SGA also impaired GH-stimulated JAK2 and STAT5 phosphorylation39. IUGR children have lower serum IGFBP3 than lean children of normal height41, while postnatal ksr2 −/− mice also show decreased IGFBP3 (Fig.…”

Section: Discussionsupporting

confidence: 61%

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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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Section: Discussionsupporting

confidence: 61%

“…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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“…GH resistance can be shown in rat models of sepsis and uremia and in small rats for gestational age (SGA) without catch-up growth. This was associated with an increased expression of SOCS-2 and CIS and impaired JAK/STAT signaling [66], [67], [68]. In our model, however, catch-up growth was associated with the overexpression of SOCS-2 and CIS in adult CH rats.…”

Section: Discussionmentioning

confidence: 50%

Influence of Neonatal Hypothyroidism on Hepatic Gene Expression and Lipid Metabolism in Adulthood

Santana-Farré¹,

Mirecki-Garrido²,

Bocos

et al. 2012

PLoS ONE

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Thyroid hormones are required for normal growth and development in mammals. Congenital-neonatal hypothyroidism (CH) has a profound impact on physiology, but its specific influence in liver is less understood. Here, we studied how CH influences the liver gene expression program in adulthood. Pregnant rats were given the antithyroid drug methimazole (MMI) from GD12 until PND30 to induce CH in male offspring. Growth defects due to CH were evident as reductions in body weight and tail length from the second week of life. Once the MMI treatment was discontinued, the feed efficiency increased in CH, and this was accompanied by significant catch-up growth. On PND80, significant reductions in body mass, tail length, and circulating IGF-I levels remained in CH rats. Conversely, the mRNA levels of known GH target genes were significantly upregulated. The serum levels of thyroid hormones, cholesterol, and triglycerides showed no significant differences. In contrast, CH rats showed significant changes in the expression of hepatic genes involved in lipid metabolism, including an increased transcription of PPARα and a reduced expression of genes involved in fatty acid and cholesterol uptake, cellular sterol efflux, triglyceride assembly, bile acid synthesis, and lipogenesis. These changes were associated with a decrease of intrahepatic lipids. Finally, CH rats responded to the onset of hypothyroidism in adulthood with a reduction of serum fatty acids and hepatic cholesteryl esters and to T3 replacement with an enhanced activation of malic enzyme. In summary, we provide in vivo evidence that neonatal hypothyroidism influences the hepatic transcriptional program and tissue sensitivity to hormone treatment in adulthood. This highlights the critical role that a euthyroid state during development plays on normal liver physiology in adulthood.

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“…Reduced growth, IGF-I response and IS observed in children in the highest baseline IGF-I tertiles may suggest relative resistance to multiple hormones, a proposed mechanism for developmental programming [39] or a defect common to insulin and IGF-I signalling. Furthermore, impairments in GH signalling pathways for hepatic IGF-I generation and downregulation of peripheral IGF-I receptor have been demonstrated in experimental intrauterine growth retardation animal models [16,40,41]. …”

Section: Discussionmentioning

confidence: 99%

Baseline IGF-I Levels Determine Insulin Secretion and Insulin Sensitivity during the First Year on Growth Hormone Therapy in Children Born Small for Gestational Age. Results from a North European Multicentre Study (NESGAS)

Jensen

Thankamony²,

O’Çonnell³

et al. 2013

Horm Res Paediatr

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Objective: Developmental programming alters growth and metabolic outcome in children born small for gestational age (SGA). We explored insulin and glucose metabolism in SGA children treated with a fixed GH dose over 1 year. Methods: In the North European Small for Gestational Age Study (NESGAS), 110 short SGA children received GH at 67 µg/kg/day for 1 year. Insulin secretion was assessed by acute insulin response (AIR), insulin sensitivity (IS) by HOMA and disposition index (DI) by insulin secretion adjusted for IS. Results: First-year GH therapy led to increases in height and IGF-I standard deviation score (SDS), and reductions in IS (p < 0.0001). Compensatory increases in AIR (p < 0.0001) were insufficient and resulted in reduced DI (p = 0.032). Children in the highest IGF-I SDS tertile at baseline were the least insulin sensitive at baseline (p = 0.024) and 1 year (p = 0.006). IGF-I responses after 1 year were positively related to AIR (r = 0.30, p = 0.007) and DI (r = 0.29, p = 0.005). Conclusion: In SGA children treated with a high GH dose for 1 year, baseline IGF-I levels were related to IS whilst gains in height and IGF-I responses were associated with insulin secretion. Defining heterogeneity in IGF-I in SGA children may be useful in predicting growth and metabolic response.

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

Cited by 11 publications

References 70 publications

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

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

Influence of Neonatal Hypothyroidism on Hepatic Gene Expression and Lipid Metabolism in Adulthood

Baseline IGF-I Levels Determine Insulin Secretion and Insulin Sensitivity during the First Year on Growth Hormone Therapy in Children Born Small for Gestational Age. Results from a North European Multicentre Study (NESGAS)

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