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

• Published in: Endocrinology (Philadelphia) 2017-07, Vol.158 (7), p.2269-2283
• Main Authors: François, Jean-Christophe, Aïd, Saba, Chaker, Zayna, Lacube, Philippe, Xu, Jie, Fayad, Racha, Côté, Francine, Even, Patrick, Holzenberger, Martin
• Format: Article
• Language: English
• Subjects: Acromegaly; Age related diseases; Aging; Animal tissues; Animals; Biochemistry, Molecular Biology; Body composition; Body Composition - drug effects; Body Composition - genetics; Body size; Cancer; Cellular Biology; Cognition; Endocrinology; Endocrinology and metabolism; Energy expenditure; Energy metabolism; Energy Metabolism - drug effects; Energy Metabolism - genetics; Female; Gene Deletion; Genomics; Growth factors; Growth Hormone - metabolism; Growth hormones; Human Growth Hormone - analogs & derivatives; Human Growth Hormone - pharmacology; Human health and pathology; Insulin; Insulin Resistance - genetics; Insulin-like growth factor I; Insulin-Like Growth Factor I - antagonists & inhibitors; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factor I receptors; Insulin-like growth factors; Life Sciences; Life span; Long-term effects; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular biology; Neurodegeneration; Physiological effects; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - genetics; Rodents; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; Subcellular Processes; Thinness - genetics; Thinness - metabolism
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2017-00261

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.Mice with ubiquitous adult IGF-1R knockout were strikingly lean and showed coordinate changes in body composition. Cognition was normal but beneficial metabolic effects contrasted with upregulated GH.