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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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Exploration of Adult Energy Metabolism(A) bIGF1RKO+/− adipocytes from inguinal AT were abnormally enlarged.(B) Leptinemia was very high in bIGF1RKO+/− mice, and strongly correlated with individual total AT size in all animals (R = 0.76, p < 0.0001, n = 82).(C) Glucose tolerance was impaired in bIGF1RKO+/− males and females.(D) 30 min after intraperitoneal glucose injection (T30), the plasma insulin concentration was, as expected, significantly increased in mutants and controls. However, although bIGF1RKO+/− females responded to elevated blood glucose with adequate hyperinsulinemia, bIGF1RKO+/− males did not, suggesting a secretory defect.
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pbio-0060254-g005: Exploration of Adult Energy Metabolism(A) bIGF1RKO+/− adipocytes from inguinal AT were abnormally enlarged.(B) Leptinemia was very high in bIGF1RKO+/− mice, and strongly correlated with individual total AT size in all animals (R = 0.76, p < 0.0001, n = 82).(C) Glucose tolerance was impaired in bIGF1RKO+/− males and females.(D) 30 min after intraperitoneal glucose injection (T30), the plasma insulin concentration was, as expected, significantly increased in mutants and controls. However, although bIGF1RKO+/− females responded to elevated blood glucose with adequate hyperinsulinemia, bIGF1RKO+/− males did not, suggesting a secretory defect.

Mentions: Weight gain with age was slightly greater for adult bIGF1RKO+/− mice than for controls (unpublished data), such that female mutants finally attained the same weight as controls. We analyzed body composition in 10-mo-old animals, and as suggested by growth curves and circulating IGF-I levels, most organs in bIGF1RKO+/− mice were smaller than those in controls (Table S1). Adipose tissue (AT), in contrast, was significantly enlarged in males and females (Figure 5A; Table S2). In both sexes, the largest increase was in subcutaneous AT, whereas visceral AT was less increased in mutant females, and even slightly diminished in males, similar to other GH-deficient mouse models [30–32]. Accordingly, circulating leptin levels were excessive in bIGF1RKO+/− mice (males, 27.1 ± 3.6 ng/ml versus 7.4 ± 1.2 ng/ml; females, 15.5 ± 1.0 ng/ml versus 6.5 ± 0.5 ng/ml; both p < 0.0001; Figure 5B). At age 4 mo, blood biochemistry in bIGF1RKO+/− mice was still normal (Table S3), but at 10 mo, HDL and total cholesterol concentrations were high (unpublished data) and triglyceride (TG) and free fatty acid (FFA) concentrations in males significantly higher than in controls, probably due to the abundance of AT (TG, 1.36 ± 0.12 mmol/l versus 1.03 ± 0.09 mmol/l, n = 10 per group, p < 0.05; FFA, 0.65 ± 0.04 mmol/l versus 0.48 ± 0.03 mmol/l, n = 10 per group, p < 0.005). As circulating GH counteracts fat storage, these metabolic traits may be secondary to the observed somatotropic defect.


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)

Exploration of Adult Energy Metabolism(A) bIGF1RKO+/− adipocytes from inguinal AT were abnormally enlarged.(B) Leptinemia was very high in bIGF1RKO+/− mice, and strongly correlated with individual total AT size in all animals (R = 0.76, p < 0.0001, n = 82).(C) Glucose tolerance was impaired in bIGF1RKO+/− males and females.(D) 30 min after intraperitoneal glucose injection (T30), the plasma insulin concentration was, as expected, significantly increased in mutants and controls. However, although bIGF1RKO+/− females responded to elevated blood glucose with adequate hyperinsulinemia, bIGF1RKO+/− males did not, suggesting a secretory defect.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-0060254-g005: Exploration of Adult Energy Metabolism(A) bIGF1RKO+/− adipocytes from inguinal AT were abnormally enlarged.(B) Leptinemia was very high in bIGF1RKO+/− mice, and strongly correlated with individual total AT size in all animals (R = 0.76, p < 0.0001, n = 82).(C) Glucose tolerance was impaired in bIGF1RKO+/− males and females.(D) 30 min after intraperitoneal glucose injection (T30), the plasma insulin concentration was, as expected, significantly increased in mutants and controls. However, although bIGF1RKO+/− females responded to elevated blood glucose with adequate hyperinsulinemia, bIGF1RKO+/− males did not, suggesting a secretory defect.
Mentions: Weight gain with age was slightly greater for adult bIGF1RKO+/− mice than for controls (unpublished data), such that female mutants finally attained the same weight as controls. We analyzed body composition in 10-mo-old animals, and as suggested by growth curves and circulating IGF-I levels, most organs in bIGF1RKO+/− mice were smaller than those in controls (Table S1). Adipose tissue (AT), in contrast, was significantly enlarged in males and females (Figure 5A; Table S2). In both sexes, the largest increase was in subcutaneous AT, whereas visceral AT was less increased in mutant females, and even slightly diminished in males, similar to other GH-deficient mouse models [30–32]. Accordingly, circulating leptin levels were excessive in bIGF1RKO+/− mice (males, 27.1 ± 3.6 ng/ml versus 7.4 ± 1.2 ng/ml; females, 15.5 ± 1.0 ng/ml versus 6.5 ± 0.5 ng/ml; both p < 0.0001; Figure 5B). At age 4 mo, blood biochemistry in bIGF1RKO+/− mice was still normal (Table S3), but at 10 mo, HDL and total cholesterol concentrations were high (unpublished data) and triglyceride (TG) and free fatty acid (FFA) concentrations in males significantly higher than in controls, probably due to the abundance of AT (TG, 1.36 ± 0.12 mmol/l versus 1.03 ± 0.09 mmol/l, n = 10 per group, p < 0.05; FFA, 0.65 ± 0.04 mmol/l versus 0.48 ± 0.03 mmol/l, n = 10 per group, p < 0.005). As circulating GH counteracts fat storage, these metabolic traits may be secondary to the observed somatotropic defect.

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