ISR-DEPENDENT METABOLIC REGULATION

The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation‐dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand‐activated skeletal muscle–specific derivative of the eIF2α protein kinase R‐like ER kinase revealed the expected up‐regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small‐molecule ISR activator that promoted Fgf21 expression in cell‐based screens and by implication of the ISR‐inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell‐autonomous proteostasis and amino acid metabolism, but also affects non‐cell‐autonomous metabolic regulation by induced expression of a potent myokine.—Miyake, M., Nomura, A., Ogura, A., Takehana, K., Kitahara, Y., Takahara, K., Tsugawa, K., Miyamoto, C., Miura, N., Sato, R., Kurahashi, K., Harding, H. P., Oyadomari, M., Ron, D., Oyadomari, S. Skeletal muscle‐specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21‐mediated non‐cell‐autonomous energy metabolism

Skeletal muscle–specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21–mediated non–cell-autonomous energy metabolism

The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand-activated skeletal muscle-specific derivative of the eIF2α protein kinase R-like ER kinase revealed the expected up-regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small-molecule ISR activator that promoted Fgf21 expression in cell-based screens and by implication of the ISR-inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell-autonomous proteostasis and amino acid metabolism, but also affects non-cell-autonomous metabolic regulation by induced expression of a potent myokine.Ministry of Education, Culture, Sports, Science and Culture (MEXT) of Japan Inoue Foundation for Science Mitsubishi Foundation Uehara Memorial Foundation Naito Foundation Cell Science Research Foundation Takeda Science Foundation Sankyo Foundation Ono Medical Research Foundation Mochida Memorial Foundation Ube Foundation Kowa Life Science Foundation Suzuken Memorial Foundation Kanae Foundation Japan Diabetes Foundation Japan Society for Promotion of Science (JSPS) EU FP7. Grant Number: 277713 Wellcome Trust. Grant Number: 084812/Z/08/

Monte Carlo Modeling of Shortwave-Infrared Fluorescence Photon Migration in Voxelized Media for the Detection of Breast Cancer

Recent progress regarding shortwave-infrared (SWIR) molecular imaging technology has inspired another modality of noninvasive diagnosis for early breast cancer detection in which previous mammography or sonography would be compensated. Although a SWIR fluorescence image of a small breast cancer of several millimeters was obtained from experiments with small animals, detailed numerical analyses before clinical application were required, since various parameters such as size as well as body hair differed between humans and small experimental animals. In this study, the feasibility of SWIR was compared against visible (VIS) and near-infrared (NIR) region, using the Monte Carlo simulation in voxelized media. In this model, due to the implementation of the excitation gradient, fluorescence is based on rational mechanisms, whereas fluorescence within breast cancer is spatially proportional to excitation intensity. The fluence map of SWIR simulation with excitation gradient indicated signals near the upper surface of the cancer, and stronger than those of the NIR. Furthermore, there was a dependency on the fluence signal distribution on the contour of the breast tissue, as well as the internal structure, due to the implementation of digital anatomical data for the Visible Human Project. The fluorescence signal was observed to become weaker in all regions including the VIS, the NIR, and the SWIR region, when fluorescence-labeled cancer either became smaller or was embedded in a deeper area. However, fluorescence in SWIR alone from a cancer of 4 mm diameter was judged to be detectable at a depth of 1.4 cm