Abstract
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.
Highlights
In addition to its role as a scaffold for ERK signaling, Kinase suppressor of Ras 2 (KSR2) interacts with and regulates the energy sensor 5′-AMP-activated protein kinase (AMPK), an interaction that is a critical contributor to energy balance[12]
The growth defect is more severe in ksr2−/− animals with the DBA/1LacJ background, which are about 50% the weight of their wild type (WT) littermates at ages PN14-17 12
To determine if altered insulin-like growth factor 1 (IGF-1) expression contributes to the neonatal growth and bone defects in ksr2−/− mice, serum growth hormone (GH) and IGF-1 levels in PN6 and postnatal day 17 (PN17) WT and ksr2−/− mice were measured by ELISA
Summary
In addition to its role as a scaffold for ERK signaling, KSR2 interacts with and regulates the energy sensor 5′-AMP-activated protein kinase (AMPK), an interaction that is a critical contributor to energy balance[12]. Ksr2−/− mice recapitulate the key metabolic characteristics of humans with KSR2 mutations; ksr2−/− mice are obese, insulin-resistant, and exhibit a reduced metabolic rate[12]. These observations suggest a conserved function of KSR2 between rodents and humans. In response to poor nutrition, the body induces GH resistance in order to decrease circulating IGF-1 and reduce growth and energy demand[21]. Exogenous IGF-1 rescued bone development, and failed to restore normal body weight to neonatal ksr2−/− mice. Elucidating the mechanisms underlying growth defects in neonatal ksr2−/− mice may help reveal mechanisms critical to the development of normal adult energy balance and glucose homeostasis
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