IGF1R is a mediator of sex-specific metabolism in mice: Effects of age and high-fat diet
Patricia Pérez‐Matute, Icíar P. López, María Íñiguez, Emma Recio‐Fernández, Raquel Torrens, Sergio Piñeiro‐Hermida, Elvira Alfaro‐Arnedo, Luong Chau, Christina Walz, Andreas Hoeflich, José A. Oteo, José G. Pichel
Abstract
Objective We aimed to investigate the short and long-term metabolic consequences of IGF1R systemic gene deficiency in mice. Methods UBC-CreERT2, Igf1r fl/fl mutant mice were used to suppress IGF1R signaling in adult tissues by inducing postnatal generalized Igf1r deletion with tamoxifen. Animals were analyzed at two different ages: i ) 13-weeks old young mice, and ii ) 12-months old middle-aged mice. In addition, the effects of 10 weeks-long high-fat diet (HFD) were investigated in middle-aged mice. Results Young IGF1R-deficient mice were insulin-resistant, with high IGF1, growth hormone (GH) and IGFBP3, as well as low IGFBP2 circulating levels. Males also presented increased triglycerides in liver. In contrast, middle-aged mice did not clearly show all of these alterations, suggesting possible compensatory effects. Middle-aged IGF1R-deficient male mice were able to counteract the negative effects induced by aging and HFD in adiposity, inflammation and glucose metabolism. A metabolic sexual dimorphism dependent on IGF1R was observed, especially in middle-aged mice. Conclusions These results demonstrate that IGF1R is involved in metabolic homeostasis, with effects modulated by diet-induced obesity and aging in a sex dependent manner. Thus, IGF1R deficiency in mice is proposed as a useful tool to understand metabolic alterations observed in patients with IGF1R gene deletions.