Bahareh Hekmatnejad, Vionnie W.C. Yu, William Addison, Vice Mandic, Martin Pellicelli, Alice Arabian, and René St-Arnaud
FIAT (Factor Inhibiting ATF4-mediated Transcription) interacts with ATF4 to repress its transcriptional activity. We performed a phenotypic analysis of Fiat-deficient male mice (Fiat-/Y) at 8 and 16 weeks of age. Fiat-/Y mice appeared normal at birth and weight gain was comparable between genotypes. μCT analysis of proximal femur demonstrated 46% and 13% age-dependent increases in trabecular bone volume and thickness, respectively, in Fiat-/Y mice. Cortical bone measurements at the femoral midshaft revealed a significant increase in cortical thickness in older Fiat-/Y mice. Bone gain was related to increased mineral apposition rate and increased osteoblast function. Mechanical testing showed a significant increase in femoral stiffness and strength in Fiat-/Y compared to WT. We also investigated whether FIAT contributes to metabolic functions. On standard mouse chow, Fiat-/Y animals were glucose-tolerant. However, when fed a high-fat diet (HFD) for 8 weeks, Fiat-/Y mice gained more weight than control mice, with a specific increase in white adipose tissue fat mass. The increase in fat mass was due to reduced energy expenditure, which was correlated with reduced fatty acid oxidation and lipolysis in the adipose tissue of mutant mice. The expression of the Scd1 gene, involved in lipogenesis, was upregulated in the subcutaneous adipose tissue of Fiat-/Y animals. Moreover, HFD-fed Fiat-/Y mice exhibited increased circulating leptin and insulin levels relative to WT animals, demonstrating that endocrine abnormalities associated with the disturbance in energy balance. We conclude that Fiat-/Y mice exhibit an anabolic bone phenotype but display increased susceptibility to develop metabolic-related disorders on a HFD.