共查询到20条相似文献,搜索用时 46 毫秒
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Yoon JC Puigserver P Chen G Donovan J Wu Z Rhee J Adelmant G Stafford J Kahn CR Granner DK Newgard CB Spiegelman BM 《Nature》2001,413(6852):131-138
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A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange 总被引:3,自引:0,他引:3
Liu Y Dentin R Chen D Hedrick S Ravnskjaer K Schenk S Milne J Meyers DJ Cole P Yates J Olefsky J Guarente L Montminy M 《Nature》2008,456(7219):269-273
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Puigserver P Rhee J Donovan J Walkey CJ Yoon JC Oriente F Kitamura Y Altomonte J Dong H Accili D Spiegelman BM 《Nature》2003,423(6939):550-555
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Wang Y Li G Goode J Paz JC Ouyang K Screaton R Fischer WH Chen J Tabas I Montminy M 《Nature》2012,485(7396):128-132
In the fasted state, increases in circulating glucagon promote hepatic glucose production through induction of the gluconeogenic program. Triggering of the cyclic AMP pathway increases gluconeogenic gene expression via the de-phosphorylation of the CREB co-activator CRTC2 (ref. 1). Glucagon promotes CRTC2 dephosphorylation in part through the protein kinase A (PKA)-mediated inhibition of the CRTC2 kinase SIK2. A number of Ser/Thr phosphatases seem to be capable of dephosphorylating CRTC2 (refs 2, 3), but the mechanisms by which hormonal cues regulate these enzymes remain unclear. Here we show in mice that glucagon stimulates CRTC2 dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent Ser/Thr-phosphatase calcineurin (also known as PP3CA). Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP(3)Rs), which associate with CRTC2. After their activation, InsP(3)Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signalling reduced CRTC2 activity via the AKT-mediated inactivation of InsP(3)Rs. InsP(3)R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic downregulation of InsP(3)Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrate how interactions between cAMP and calcium pathways at the level of the InsP(3)R modulate hepatic glucose production under fasting conditions and in diabetes. 相似文献
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Sahin E Colla S Liesa M Moslehi J Müller FL Guo M Cooper M Kotton D Fabian AJ Walkey C Maser RS Tonon G Foerster F Xiong R Wang YA Shukla SA Jaskelioff M Martin ES Heffernan TP Protopopov A Ivanova E Mahoney JE Kost-Alimova M Perry SR Bronson R Liao R Mulligan R Shirihai OS Chin L DePinho RA 《Nature》2011,470(7334):359-365
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The lipid phosphatase SHIP2 controls insulin sensitivity 总被引:17,自引:0,他引:17
Clément S Krause U Desmedt F Tanti JF Behrends J Pesesse X Sasaki T Penninger J Doherty M Malaisse W Dumont JE Le Marchand-Brustel Y Erneux C Hue L Schurmans S 《Nature》2001,409(6816):92-97
Insulin is the primary hormone involved in glucose homeostasis, and impairment of insulin action and/or secretion has a critical role in the pathogenesis of diabetes mellitus. Type-II SH2-domain-containing inositol 5-phosphatase, or 'SHIP2', is a member of the inositol polyphosphate 5-phosphatase family. In vitro studies have shown that SHIP2, in response to stimulation by numerous growth factors and insulin, is closely linked to signalling events mediated by both phosphoinositide-3-OH kinase and Ras/mitogen-activated protein kinase. Here we report the generation of mice lacking the SHIP2 gene. Loss of SHIP2 leads to increased sensitivity to insulin, which is characterized by severe neonatal hypoglycaemia, deregulated expression of the genes involved in gluconeogenesis, and perinatal death. Adult mice that are heterozygous for the SHIP2 mutation have increased glucose tolerance and insulin sensitivity associated with an increased recruitment of the GLUT4 glucose transporter and increased glycogen synthesis in skeletal muscles. Our results show that SHIP2 is a potent negative regulator of insulin signalling and insulin sensitivity in vivo. 相似文献
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Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres 总被引:62,自引:0,他引:62
Lin J Wu H Tarr PT Zhang CY Wu Z Boss O Michael LF Puigserver P Isotani E Olson EN Lowell BB Bassel-Duby R Spiegelman BM 《Nature》2002,418(6899):797-801
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A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence 总被引:130,自引:0,他引:130
G A Gonzalez K K Yamamoto W H Fischer D Karr P Menzel W Biggs W W Vale M R Montminy 《Nature》1989,337(6209):749-752