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Endocrinology. 2017 Jul 1;158(7):2269-2283. doi: 10.1210/en.2017-00261.

Disrupting IGF Signaling in Adult Mice Conditions Leanness, Resilient Energy Metabolism, and High Growth Hormone Pulses.

Author information

1
INSERM Research Center Unité 938, 75012 Paris, France.
2
Sorbonne University, 75005 Paris, France.
3
Faculty of Medicine, University Paris Descartes, 75006 Paris, France.
4
Institut Imagine INSERM Unité 1163/CNRS Equipe 8254, Necker Enfants Malades Hospital, 75015 Paris, France.
5
AgroParisTech, INRA, Université Paris Saclay, Nutrition Physiology and Ingestive Behavior Unité 914, 75005 Paris, France.

Abstract

Growth hormone (GH) and insulinlike growth factor (IGF) promote aging and age-related pathologies. Inhibiting this pathway by targeting IGF receptor (IGF-1R) is a promising strategy to extend life span, alleviate age-related diseases, and reduce tumor growth. Although anti-IGF-1R agents are being developed, long-term effects of IGF-1R blockade remain unknown. In this study, we used ubiquitous inducible IGF-1R knockout (UBIKOR) to suppress signaling in all adult tissues and screened health extensively. Surprisingly, UBIKOR mice showed no overt defects and presented with rather inconspicuous health, including normal cognition. Endocrine GH and IGF-1 were strongly upregulated without causing acromegaly. UBIKOR mice were strikingly lean with coordinate changes in body composition and organ size. They were insulin resistant but preserved physiological energy expenditure and displayed enhanced fasting metabolic flexibility. Thus, long-term IGF-1R blockade generated beneficial effects on aging-relevant metabolism, but exposed to high GH. This needs to be considered when targeting IGF-1R to protect from neurodegeneration, retard aging, or fight cancer.

PMID:
28881863
DOI:
10.1210/en.2017-00261
[Indexed for MEDLINE]

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