The roles of ATF3 in glucose homeostasis - A transgenic mouse model with liver dysfunction and defects in endocrine pancreas

Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP-respon se element-binding protein family of transcription factors. It is a transcr iptional repressor, and the expression of its corresponding gene is induced by stress signals in a variety of tissues, including the liver. In this re port, we demonstrate that ATF3 is induced in the pancreas by partial pancre atectomy, streptozotocin treatment, and ischemia coupled with reperfusion. Furthermore, ATF3 is induced in cultured islet cells by oxidative stress. I nterestingly, transgenic mice expressing ATF3 in the liver and pancreas und er the control of the transthyretin promoter have defects in glucose homeos tasis and perinatal lethality. We present evidence that expression of ATF3 in the liver represses the expression of genes encoding gluconeogenic enzym es. Furthermore, expression of ATF3 in the pancreas leads to abnormal endoc rine pancreas and reduced numbers of hormone-producing cells. Analyses of e mbryos indicated that the ATF3 transgene is expressed in the ductal epithel ium in the developing pancreas, and the transgenic pancreas has fewer mitot ic cells than the non-transgenic counterpart, providing a potential explana tion for the reduction of endocrine cells. Because ATF3 is a stress-inducib le gene, these mice may represent a model to investigate the molecular mech anisms for some stress-associated diseases.