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Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.

Kappeler L, De Magalhaes Filho C, Dupont J, Leneuve P, Cervera P, Périn L, Loudes C, Blaise A, Klein R, Epelbaum J, Le Bouc Y, Holzenberger M - PLoS Biol. (2008)

Bottom Line: Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals.The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments.Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

View Article: PubMed Central - PubMed

Affiliation: INSERM U893, Hôpital Saint-Antoine, Paris, France.

ABSTRACT
Mutations that decrease insulin-like growth factor (IGF) and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R) efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

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Somatotropic Signals in the Hypothalamic-Pituitary Complex(A) Efficient Cre-lox recombination in hypothalamus, not in pituitary, as shown by X-Gal-staining of a sagittal NesCre+/0;Rosa26R+/0 brain section: the anterior pituitary originates from the pharyngeal wall, not from neuroepithelium, to which NesCre transgene expression is confined. Abbreviations: 3V, third ventricle; aP, anterior pituitary; Bo, bone; Hpt, hypothalamus; Inf, infundibulum; iP, intermediate pituitary; ME, median eminence; pP, posterior pituitary; R, recessus of the third ventricle. PCR analysis of genomic DNA confirmed absence of recombination from the pituitary: intact Igf1rflox alleles in pituitary, and knockout (Igf1r−) alleles prevalent in hypothalamus.(B) GHRH immunoreactivity (red) at nerve endings in the ME was weaker than control in bIGF1RKO+/− mice (65 ± 6 versus 122 ± 10 au (arbitrary units), p < 0.01, n = 3), whereas SRIH (green) was unaffected (191 ± 3 versus 197 ± 5 au, n = 3). Briefly, ME tissue sections from the same anatomical location in three bIGF1RKO+/− and three control 10-day-old males were subjected to IHC. Micrographs were taken under identical conditions. For each animal, data from ten sections were averaged. The ratio of GHRH to SRIH immunoreactivity was lower in bIGF1RKO+/− than in control animals (0.34 ± 0.05 versus 0.54 ± 0.09, n = 6; p = 0.06).(C) Similarly, GHRH gene expression (measured by quantitative real-time RT-PCR, relative to β-actin) was lower at age 10 d in mutants than controls.(D) SRIH expression was similar in mutants and controls.(E) Pit-1 expression (relative to 18S rRNA) was lower in bIGF1RKO+/− than wild-type pituitaries at age 10 d.
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pbio-0060254-g003: Somatotropic Signals in the Hypothalamic-Pituitary Complex(A) Efficient Cre-lox recombination in hypothalamus, not in pituitary, as shown by X-Gal-staining of a sagittal NesCre+/0;Rosa26R+/0 brain section: the anterior pituitary originates from the pharyngeal wall, not from neuroepithelium, to which NesCre transgene expression is confined. Abbreviations: 3V, third ventricle; aP, anterior pituitary; Bo, bone; Hpt, hypothalamus; Inf, infundibulum; iP, intermediate pituitary; ME, median eminence; pP, posterior pituitary; R, recessus of the third ventricle. PCR analysis of genomic DNA confirmed absence of recombination from the pituitary: intact Igf1rflox alleles in pituitary, and knockout (Igf1r−) alleles prevalent in hypothalamus.(B) GHRH immunoreactivity (red) at nerve endings in the ME was weaker than control in bIGF1RKO+/− mice (65 ± 6 versus 122 ± 10 au (arbitrary units), p < 0.01, n = 3), whereas SRIH (green) was unaffected (191 ± 3 versus 197 ± 5 au, n = 3). Briefly, ME tissue sections from the same anatomical location in three bIGF1RKO+/− and three control 10-day-old males were subjected to IHC. Micrographs were taken under identical conditions. For each animal, data from ten sections were averaged. The ratio of GHRH to SRIH immunoreactivity was lower in bIGF1RKO+/− than in control animals (0.34 ± 0.05 versus 0.54 ± 0.09, n = 6; p = 0.06).(C) Similarly, GHRH gene expression (measured by quantitative real-time RT-PCR, relative to β-actin) was lower at age 10 d in mutants than controls.(D) SRIH expression was similar in mutants and controls.(E) Pit-1 expression (relative to 18S rRNA) was lower in bIGF1RKO+/− than wild-type pituitaries at age 10 d.

Mentions: To study the role of IGF signaling in the CNS, we generated mice with heterozygous and homozygous brain-specific IGF-1 receptor knockout mutations (bIGF1RKO+/− and bIGF1RKO−/−) by conditional mutagenesis (Figure 1A and 1B). Mutants and their controls were littermates with identical genetic background, and matings were performed such that the Nestin-Cre transgene was always paternally transmitted (see Methods and Text S1 for breeding and genetic background). Homozygous mutants (bIGF1RKO−/−) have no IGF-1R on CNS neurons or glia. They were microcephalic and developed a complex phenotype involving severe growth retardation, infertility, and abnormal behavior (Figure S1). Though very interesting per se, the homozygous bIGF1RKO−/− mice did not show extended lifespan and their adult plasma IGF-I concentration was significantly higher than control values (Figure S1E and S1G). Thus, homozygous mutants were not a suitable model for healthy longevity, which is generally associated with diminished insulin-like signaling [20,21]. We therefore studied the heterozygous mutants (bIGF1RKO+/−), in which the IGF-1R levels in the CNS are half that in the wild-type (Figure 1C). They were healthy and behaved normally (Figure S2). Their body growth, however, though initially normal, was progressively retarded from 20 d of age onwards (Figure 2A). By age 90 d, bIGF1RKO+/− adults weighed about 90% of controls (males, 30.5 ± 0.6 g, n = 12 versus 33.7 ± 0.4 g, −9.6%, n = 19, p < 0.0001; females, 24.1 ± 0.3 g, n = 18 versus 26.2 ± 0.5 g, −7.9%, n = 14, p < 0.001) and were 5% shorter than controls (p < 0.001) (Table S1). bIGF1RKO+/− mice had normal IGF-1R levels in peripheral tissues (see Figure 1C), so we speculated that endocrine growth regulation during development was disturbed. bIGF1RKO+/− pituitaries were indeed small from age 10 d onwards (Figure 2B), and total GH content remained low throughout development (Figure 2C). The GH concentration per milligram protein fell at age 20 d, suggesting that retardation of early postnatal somatotroph differentiation (Figure 2D) started between day 10 and day 20. Plasma IGF-I, which strongly depends on GH, did not show any pubertal increase in bIGF1RKO+/− mice while controls displayed the normal surge (Figure 2E). Moreover, the concentration of the acid labile subunit (ALS), an important regulator of IGF-I stability and itself regulated by GH, was very low in mutants throughout postnatal life (Figure 2F). Importantly, in this model the IGF-1R gene is knocked out in the hypothalamus but not in the pituitary (Figure 3A). Therefore, we suspected that this somatotropic phenotype was caused by alterations in GH-regulatory neurons of the hypothalamus, i.e. arcuate nucleus GHRH neurons and anterior periventricular somatostatin (SRIH) neurons whose endings converge on the external layer of the median eminence (ME). Indeed, hypothalamic GHRH expression in bIGF1RKO+/− mice was significantly low, and GHRH accumulation in the GHRH neuron endings was clearly diminished around age 10 d (Figure 3B and 3C). In contrast, hypophysiotropic SRIH-producing neurons in the hypothalamus exhibited a normal abundance of SRIH at age 10 d, evidence of the cell-specificity of this phenotype (Figure 3B and 3D). Accordingly, Pit-1 expression, which is controlled by GHRH neurons and steers somatotropic cell differentiation, was half normal in mutant pituitaries (Figure 3E).


Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism.

Kappeler L, De Magalhaes Filho C, Dupont J, Leneuve P, Cervera P, Périn L, Loudes C, Blaise A, Klein R, Epelbaum J, Le Bouc Y, Holzenberger M - PLoS Biol. (2008)

Somatotropic Signals in the Hypothalamic-Pituitary Complex(A) Efficient Cre-lox recombination in hypothalamus, not in pituitary, as shown by X-Gal-staining of a sagittal NesCre+/0;Rosa26R+/0 brain section: the anterior pituitary originates from the pharyngeal wall, not from neuroepithelium, to which NesCre transgene expression is confined. Abbreviations: 3V, third ventricle; aP, anterior pituitary; Bo, bone; Hpt, hypothalamus; Inf, infundibulum; iP, intermediate pituitary; ME, median eminence; pP, posterior pituitary; R, recessus of the third ventricle. PCR analysis of genomic DNA confirmed absence of recombination from the pituitary: intact Igf1rflox alleles in pituitary, and knockout (Igf1r−) alleles prevalent in hypothalamus.(B) GHRH immunoreactivity (red) at nerve endings in the ME was weaker than control in bIGF1RKO+/− mice (65 ± 6 versus 122 ± 10 au (arbitrary units), p < 0.01, n = 3), whereas SRIH (green) was unaffected (191 ± 3 versus 197 ± 5 au, n = 3). Briefly, ME tissue sections from the same anatomical location in three bIGF1RKO+/− and three control 10-day-old males were subjected to IHC. Micrographs were taken under identical conditions. For each animal, data from ten sections were averaged. The ratio of GHRH to SRIH immunoreactivity was lower in bIGF1RKO+/− than in control animals (0.34 ± 0.05 versus 0.54 ± 0.09, n = 6; p = 0.06).(C) Similarly, GHRH gene expression (measured by quantitative real-time RT-PCR, relative to β-actin) was lower at age 10 d in mutants than controls.(D) SRIH expression was similar in mutants and controls.(E) Pit-1 expression (relative to 18S rRNA) was lower in bIGF1RKO+/− than wild-type pituitaries at age 10 d.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2573928&req=5

pbio-0060254-g003: Somatotropic Signals in the Hypothalamic-Pituitary Complex(A) Efficient Cre-lox recombination in hypothalamus, not in pituitary, as shown by X-Gal-staining of a sagittal NesCre+/0;Rosa26R+/0 brain section: the anterior pituitary originates from the pharyngeal wall, not from neuroepithelium, to which NesCre transgene expression is confined. Abbreviations: 3V, third ventricle; aP, anterior pituitary; Bo, bone; Hpt, hypothalamus; Inf, infundibulum; iP, intermediate pituitary; ME, median eminence; pP, posterior pituitary; R, recessus of the third ventricle. PCR analysis of genomic DNA confirmed absence of recombination from the pituitary: intact Igf1rflox alleles in pituitary, and knockout (Igf1r−) alleles prevalent in hypothalamus.(B) GHRH immunoreactivity (red) at nerve endings in the ME was weaker than control in bIGF1RKO+/− mice (65 ± 6 versus 122 ± 10 au (arbitrary units), p < 0.01, n = 3), whereas SRIH (green) was unaffected (191 ± 3 versus 197 ± 5 au, n = 3). Briefly, ME tissue sections from the same anatomical location in three bIGF1RKO+/− and three control 10-day-old males were subjected to IHC. Micrographs were taken under identical conditions. For each animal, data from ten sections were averaged. The ratio of GHRH to SRIH immunoreactivity was lower in bIGF1RKO+/− than in control animals (0.34 ± 0.05 versus 0.54 ± 0.09, n = 6; p = 0.06).(C) Similarly, GHRH gene expression (measured by quantitative real-time RT-PCR, relative to β-actin) was lower at age 10 d in mutants than controls.(D) SRIH expression was similar in mutants and controls.(E) Pit-1 expression (relative to 18S rRNA) was lower in bIGF1RKO+/− than wild-type pituitaries at age 10 d.
Mentions: To study the role of IGF signaling in the CNS, we generated mice with heterozygous and homozygous brain-specific IGF-1 receptor knockout mutations (bIGF1RKO+/− and bIGF1RKO−/−) by conditional mutagenesis (Figure 1A and 1B). Mutants and their controls were littermates with identical genetic background, and matings were performed such that the Nestin-Cre transgene was always paternally transmitted (see Methods and Text S1 for breeding and genetic background). Homozygous mutants (bIGF1RKO−/−) have no IGF-1R on CNS neurons or glia. They were microcephalic and developed a complex phenotype involving severe growth retardation, infertility, and abnormal behavior (Figure S1). Though very interesting per se, the homozygous bIGF1RKO−/− mice did not show extended lifespan and their adult plasma IGF-I concentration was significantly higher than control values (Figure S1E and S1G). Thus, homozygous mutants were not a suitable model for healthy longevity, which is generally associated with diminished insulin-like signaling [20,21]. We therefore studied the heterozygous mutants (bIGF1RKO+/−), in which the IGF-1R levels in the CNS are half that in the wild-type (Figure 1C). They were healthy and behaved normally (Figure S2). Their body growth, however, though initially normal, was progressively retarded from 20 d of age onwards (Figure 2A). By age 90 d, bIGF1RKO+/− adults weighed about 90% of controls (males, 30.5 ± 0.6 g, n = 12 versus 33.7 ± 0.4 g, −9.6%, n = 19, p < 0.0001; females, 24.1 ± 0.3 g, n = 18 versus 26.2 ± 0.5 g, −7.9%, n = 14, p < 0.001) and were 5% shorter than controls (p < 0.001) (Table S1). bIGF1RKO+/− mice had normal IGF-1R levels in peripheral tissues (see Figure 1C), so we speculated that endocrine growth regulation during development was disturbed. bIGF1RKO+/− pituitaries were indeed small from age 10 d onwards (Figure 2B), and total GH content remained low throughout development (Figure 2C). The GH concentration per milligram protein fell at age 20 d, suggesting that retardation of early postnatal somatotroph differentiation (Figure 2D) started between day 10 and day 20. Plasma IGF-I, which strongly depends on GH, did not show any pubertal increase in bIGF1RKO+/− mice while controls displayed the normal surge (Figure 2E). Moreover, the concentration of the acid labile subunit (ALS), an important regulator of IGF-I stability and itself regulated by GH, was very low in mutants throughout postnatal life (Figure 2F). Importantly, in this model the IGF-1R gene is knocked out in the hypothalamus but not in the pituitary (Figure 3A). Therefore, we suspected that this somatotropic phenotype was caused by alterations in GH-regulatory neurons of the hypothalamus, i.e. arcuate nucleus GHRH neurons and anterior periventricular somatostatin (SRIH) neurons whose endings converge on the external layer of the median eminence (ME). Indeed, hypothalamic GHRH expression in bIGF1RKO+/− mice was significantly low, and GHRH accumulation in the GHRH neuron endings was clearly diminished around age 10 d (Figure 3B and 3C). In contrast, hypophysiotropic SRIH-producing neurons in the hypothalamus exhibited a normal abundance of SRIH at age 10 d, evidence of the cell-specificity of this phenotype (Figure 3B and 3D). Accordingly, Pit-1 expression, which is controlled by GHRH neurons and steers somatotropic cell differentiation, was half normal in mutant pituitaries (Figure 3E).

Bottom Line: Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals.The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments.Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

View Article: PubMed Central - PubMed

Affiliation: INSERM U893, Hôpital Saint-Antoine, Paris, France.

ABSTRACT
Mutations that decrease insulin-like growth factor (IGF) and growth hormone signaling limit body size and prolong lifespan in mice. In vertebrates, these somatotropic hormones are controlled by the neuroendocrine brain. Hormone-like regulations discovered in nematodes and flies suggest that IGF signals in the nervous system can determine lifespan, but it is unknown whether this applies to higher organisms. Using conditional mutagenesis in the mouse, we show that brain IGF receptors (IGF-1R) efficiently regulate somatotropic development. Partial inactivation of IGF-1R in the embryonic brain selectively inhibited GH and IGF-I pathways after birth. This caused growth retardation, smaller adult size, and metabolic alterations, and led to delayed mortality and longer mean lifespan. Thus, early changes in neuroendocrine development can durably modify the life trajectory in mammals. The underlying mechanism appears to be an adaptive plasticity of somatotropic functions allowing individuals to decelerate growth and preserve resources, and thereby improve fitness in challenging environments. Our results also suggest that tonic somatotropic signaling entails the risk of shortened lifespan.

Show MeSH
Related in: MedlinePlus