Direct monitoring of in vivo ER stress during the development of insulin resistance with ER stress-activated indicator transgenic mice

https://doi.org/10.1016/j.bbrc.2007.11.182Get rights and content

Abstract

Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic β-cell dysfunction are the hallmarks of the disease. It has been suggested that endoplasmic reticulum (ER) stress is provoked under diabetic conditions and is possibly involved in the development of insulin resistance. In this study, using ER stress-activated indicator (ERAI) transgenic mice which express green fluorescent protein (GFP) under ER stress conditions, we directly monitored in vivo ER stress in various insulin target tissues such as liver, fat, and muscle in diabetic mice with insulin resistance induced by high fat and high sucrose (HF/HS) diet treatment. In the liver of the ERAI transgenic mice, ERAI fluorescence activity was clearly observed as early as after 4 weeks of HF/HS diet treatment, whereas it was not detected at all in the fat and muscle even after 12 weeks of HF/HS diet treatment. These results suggest that induction of ER stress is associated with the development of insulin resistance and that ER stress in the liver may facilitate the development of insulin resistance in the whole body. This is the first report to directly monitor in vivo ER stress in various insulin target tissues during the development of insulin resistance. In addition, our present results suggest that ERAI transgenic mice are very useful for evaluating in vivo ER stress, especially in the liver, during the development of insulin resistance.

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Materials and methods

ERAI transgenic mice. To directly monitor in vivo ER stress in various insulin target tissues such as liver, fat, and muscle under diabetic conditions with insulin resistance, we used ER stress-activated indicator (ERAI) transgenic mice carrying the XBP-1-delta-DBD-venus expression gene [14]. In these transgenic mice, the gene encoding venus, a variant of green fluorescent protein, is fused as a reporter downstream of a partial sequence of human XBP-1 including the ER stress-specific intron.

Insulin resistance induced by high fat and high sucrose (HF/HS) diet in ERAI transgenic mice

To directly monitor in vivo ER stress in various insulin target tissues such as liver, fat, and muscle under diabetic conditions with insulin resistance, we treated ER stress-activated indicator (ERAI) transgenic mice with a high fat and high sucrose (HF/HS) diet which is well known to induce insulin resistance. Since ERAI transgenic mice express green fluorescent protein (GFP) under ER stress conditions, we evaluated ER stress levels in various insulin target tissues during the development of

Acknowledgments

We thank Dr. Masayuki Miura (Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo) for valuable suggestions for this study. Also, we thank Dr. Helena Akiko Popiel for valuable comments on the manuscript.

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