Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity.

Proceedings of the National Academy of Sciences of the United States of America
Yiguo WangMarc Montminy

Abstract

Under fasting conditions, increases in circulating concentrations of pancreatic glucagon maintain glucose homeostasis through induction of gluconeogenic genes by the CREB coactivator CRTC2. Hepatic CRTC2 activity is elevated in obesity, although the extent to which this cofactor contributes to attendant increases in insulin resistance is unclear. Here we show that mice with a knockout of the CRTC2 gene have decreased circulating glucose concentrations during fasting, due to attenuation of the gluconeogenic program. CRTC2 was found to stimulate hepatic gene expression in part through an N-terminal CREB binding domain that enhanced CREB occupancy over relevant promoters in response to glucagon. Deletion of sequences encoding the CREB binding domain in CRTC2 (-/-) mice lowered circulating blood glucose concentrations and improved insulin sensitivity in the context of diet-induced obesity. Our results suggest that small molecules that attenuate the CREB-CRTC2 pathway may provide therapeutic benefit to individuals with type 2 diabetes.

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Citations

Jan 31, 2013·Archives of Pharmacal Research·Kyoung-Jin OhSeung-Hoi Koo
Feb 25, 2011·Nature Reviews. Molecular Cell Biology·Judith Y Altarejos, Marc Montminy
Sep 30, 2010·Proceedings of the National Academy of Sciences of the United States of America·Young-Sil YoonSeung-Hoi Koo
Apr 25, 2012·Proceedings of the National Academy of Sciences of the United States of America·Nicholette Zeliadt
Dec 6, 2012·Proceedings of the National Academy of Sciences of the United States of America·Qianyi LuoIshwar Radhakrishnan
May 15, 2013·Proceedings of the National Academy of Sciences of the United States of America·Wen-Wei TsaiMarc Montminy
May 3, 2012·The Journal of Biological Chemistry·Don-Kyu KimHueng-Sik Choi
Dec 24, 2010·Current Opinion in Clinical Nutrition and Metabolic Care·Donald B Jump
Sep 21, 2013·The Journal of Clinical Investigation·Kim RavnskjaerMarc Montminy
Jul 2, 2010·Molecular Endocrinology·Aidan S HancockCatherine L May
Apr 3, 2014·Comprehensive Physiology·Liangyou Rui
Jan 2, 2014·Nucleic Acid Therapeutics·Robert DulleaRobert Stanton
Feb 18, 2014·Virology Journal·Xiaohui TianKanghong Hu
Feb 27, 2014·Proceedings of the National Academy of Sciences of the United States of America·Ananda ChapagainMuhammad Magdi Yaqoob
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Oct 10, 2012·Trends in Endocrinology and Metabolism : TEM·Zheng Sun, Mitchell A Lazar
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