The Experts below are selected from a list of 1815 Experts worldwide ranked by ideXlab platform
Marc Montminy - One of the best experts on this subject based on the ideXlab platform.
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the creb coactivator CRTC2 promotes oncogenesis in lkb1 mutant non small cell lung cancer
Science Advances, 2019Co-Authors: Laura Rodon, Wenwei Tsai, Ezra Wiater, Robert U Svensson, Matthew G H Chun, Lillian J Eichner, Reuben J Shaw, Marc MontminyAbstract:The LKB1 tumor suppressor is often mutationally inactivated in non–small cell lung cancer (NSCLC). LKB1 phosphorylates and activates members of the AMPK family of Ser/Thr kinases. Within this family, the salt-inducible kinases (SIKs) modulate gene expression in part via the inhibitory phosphorylation of the CRTCs, coactivators for CREB (cAMP response element-binding protein). The loss of LKB1 causes SIK inactivation and the induction of the CRTCs, leading to the up-regulation of CREB target genes. We identified CRTC2 as a critical factor in LKB1-deficient NSCLC. CRTC2 is unphosphorylated and therefore constitutively activated in LKB1-mutant NSCLC, where it promotes tumor growth, in part via the induction of the inhibitor of DNA binding 1 (ID1), a bona fide CREB target gene. As ID1 expression is up-regulated and confers poor prognosis in LKB1-deficient NSCLC, our results suggest that small molecules that inhibit CRTC2 and ID1 activity may provide therapeutic benefit to individuals with NSCLC.
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Mitogenic Signals Stimulate the CREB Coactivator CRTC3 through PP2A Recruitment
Elsevier, 2019Co-Authors: Tim Sonntag, Jelena Ostojić, Joan M. Vaughan, James J. Moresco, Young-sil Yoon, John R. Yates, Marc MontminyAbstract:Summary: The second messenger 3′,5′-cyclic adenosine monophosphate (cAMP) stimulates gene expression via the cAMP-regulated transcriptional coactivator (CRTC) family of cAMP response element-binding protein coactivators. In the basal state, CRTCs are phosphorylated by salt-inducible kinases (SIKs) and sequestered in the cytoplasm by 14-3-3 proteins. cAMP signaling inhibits the SIKs, leading to CRTC dephosphorylation and nuclear translocation. Here we show that although all CRTCs are regulated by SIKs, their interactions with Ser/Thr-specific protein phosphatases are distinct. CRTC1 and CRTC2 associate selectively with the calcium-dependent phosphatase calcineurin, whereas CRTC3 interacts with B55 PP2A holoenzymes via a conserved PP2A-binding region (amino acids 380–401). CRTC3-PP2A complex formation was induced by phosphorylation of CRTC3 at S391, facilitating the subsequent activation of CRTC3 by dephosphorylation at 14-3-3 binding sites. As stimulation of mitogenic pathways promoted S391 phosphorylation via the activation of ERKs and CDKs, our results demonstrate how a ubiquitous phosphatase enables cross talk between growth factor and cAMP signaling pathways at the level of a transcriptional coactivator. : Biological Sciences; Biochemistry; Molecular Biology; Cell Biology Subject Areas: Biological Sciences, Biochemistry, Molecular Biology, Cell Biolog
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creb coactivators CRTC2 and crtc3 modulate bone marrow hematopoiesis
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Jeongho Kim, Susan Hedrick, Wenwei Tsai, Ezra Wiater, John Le Lay, Klaus H Kaestner, Mathias Leblanc, Andrew Loar, Marc MontminyAbstract:Populations of circulating immune cells are maintained in equilibrium through signals that enhance the retention or egress of hematopoietic stem cells (HSCs) from bone marrow (BM). Prostaglandin E2 (PGE2) stimulates HSC renewal and engraftment through, for example, induction of the cAMP pathway. Triggering of PGE2 receptors increases HSC survival in part via the PKA-mediated induction of the cAMP response element-binding protein (CREB) signaling pathway. PKA stimulates cellular gene expression by phosphorylating CREB at Ser133 and by promoting the dephosphorylation of the cAMP- responsive transcriptional coactivators (CRTCs). We show here that disruption of both CRTC2 and CRTC3 causes embryonic lethality, and that a single allele of either CRTC2 or CRTC3 is sufficient for viability. CRTC2 knockout mice that express one CRTC3 allele (CRTC2/3m mice) develop neutrophilia and splenomegaly in adulthood due to the up-regulation of granulocyte-colony stimulating factor (G-CSF); these effects are reversed following administration of neutralizing anti–G-CSF antiserum. Adoptive transfer of CRTC2/3m BM conferred the splenomegaly/neutrophilia phenotype in WT recipients. Targeted disruption of both CRTC2 and CRTC3 in stromal cells with a mesenchymal Prx1-Cre transgene also promoted this phenotype. Depletion of CRTC2/3 was found to decrease the expression of Suppressor of Cytokine Signaling 3 (SOCS3), leading to increases in STAT3 phosphorylation and to the induction of CEBPβ, a key regulator of the G-CSF gene. As small molecule inhibition of JAK activity disrupted CEBPβ induction and reduced G-CSF expression in CRTC2/3m stromal cells, our results demonstrate how cross-coupling between the CREB/CRTC and JAK/STAT pathways contributes to BM homeostasis.
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creb pathway links pge2 signaling with macrophage polarization
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Young-sil Yoon, Susan Hedrick, John Le Lay, Klaus H Kaestner, Bing Luan, Marc MontminyAbstract:Obesity is thought to promote insulin resistance in part via activation of the innate immune system. Increases in proinflammatory cytokine production by M1 macrophages inhibit insulin signaling in white adipose tissue. In contrast, M2 macrophages have been found to enhance insulin sensitivity in part by reducing adipose tissue inflammation. The paracrine hormone prostaglandin E2 (PGE2) enhances M2 polarization in part through activation of the cAMP pathway, although the underlying mechanism is unclear. Here we show that PGE2 stimulates M2 polarization via the cyclic AMP-responsive element binding (CREB)-mediated induction of Krupple-like factor 4 (KLF4). Targeted disruption of CREB or the cAMP-regulated transcriptional coactivators 2 and 3 (CRTC2/3) in macrophages down-regulated M2 marker gene expression and promoted insulin resistance in the context of high-fat diet feeding. As re-expression of KLF4 rescued M2 marker gene expression in CREB-depleted cells, our results demonstrate the importance of the CREB/CRTC pathway in maintaining insulin sensitivity in white adipose tissue via its effects on the innate immune system.
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hepatic insulin resistance following chronic activation of the creb coactivator CRTC2
Journal of Biological Chemistry, 2015Co-Authors: Meghan F Hogan, Shigenobu Matsumura, Kim Ravnskjaer, Mark O Huising, Rebecca L Hull, Steven E Kahn, Marc MontminyAbstract:Under fasting conditions, increases in circulating concentrations of glucagon maintain glucose homeostasis via the induction of hepatic gluconeogenesis. Triggering of the cAMP pathway in hepatocytes stimulates the gluconeogenic program via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2 and CRTC3. In parallel, decreases in circulating insulin also increase gluconeogenic gene expression via the de-phosphorylation and activation of the forkhead transcription factor FOXO1. Hepatic gluconeogenesis is increased in insulin resistance where it contributes to the attendant hyperglycemia. Whether selective activation of the hepatic CREB/CRTC pathway is sufficient to trigger metabolic changes in other tissues is unclear, however. Modest hepatic expression of a phosphorylation-defective and therefore constitutively active CRTC2S171,275A protein increased gluconeogenic gene expression under fasting as well as feeding conditions. Circulating glucose concentrations were constitutively elevated in CRTC2S171,275A-expressing mice, leading to compensatory increases in circulating insulin concentrations that enhance FOXO1 phosphorylation. Despite accompanying decreases in FOXO1 activity, hepatic gluconeogenic gene expression remained elevated in CRTC2S171,275A mice, demonstrating that chronic increases in CRTC2 activity in the liver are indeed sufficient to promote hepatic insulin resistance and to disrupt glucose homeostasis.
Robert A Screaton - One of the best experts on this subject based on the ideXlab platform.
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CRTC2 is required for β cell function and proliferation
Endocrinology, 2013Co-Authors: Chandra E Eberhard, Courtney Reeks, Robert A ScreatonAbstract:Previous work in insulinoma cell lines has established that calcineurin plays a critical role in the activation of cAMP-responsive element binding protein (Creb), a key transcription factor required for β-cell function and survival, by dephosphorylating the Creb coactivator Creb-regulated transcription coactivator (Crtc)2 at 2 regulatory sites, Ser171 and Ser275. Here, we report that CRTC2 is essential both for glucose-stimulated insulin secretion and cell survival in the β-cell. Endogenous CRTC2 activation is achieved via increasing glucose levels to the physiological feeding range, indicating that CRTC2 is a sensor that couples ambient glucose concentrations to Creb activity in the β-cell. Immunosuppressant drugs such as cyclosporin A and tacrolimus that target the protein phosphatase calcineurin are commonly administered after organ transplantation. Chronic use is associated with reduced insulin secretion and new onset diabetes, suggestive of pancreatic β-cell dysfunction. Importantly, we show that ove...
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inositol 1 4 5 trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes
Nature, 2012Co-Authors: Yiguo Wang, Robert A Screaton, Jason Goode, Jose C Paz, Kunfu Ouyang, Wolfgang H Fischer, Ju Chen, Ira Tabas, Marc MontminyAbstract: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.
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inositol 1 4 5 trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes
Nature, 2012Co-Authors: Yiguo Wang, Robert A Screaton, Jason Goode, Kunfu Ouyang, Wolfgang H Fischer, Ju Chen, Ira Tabas, Gang Li, Marc MontminyAbstract:Interactions between cyclic AMP and calcium signalling pathways mediated by the inositol 1,4,5-trisphosphate receptor are shown to regulate hepatic gluconeogenesis in fasting and diabetes. During fasting, glucose production in the liver is stimulated through an increase in blood glucagon levels, and the cyclic AMP pathway increases gluconeogenic gene expression through activation of the CREB co-activator CRTC2. This study demonstrates interplay between cyclic AMP and calcium signalling pathways, and the participation of inositol-1,4,5-trisphosphate receptors in regulating CRTC2 and hepatic gluconeogenesis under fasting conditions and in diabetes. 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 (InsP3Rs), which associate with CRTC2. After their activation, InsP3Rs 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 InsP3Rs. InsP3R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic downregulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrate how interactions between cAMP and calcium pathways at the level of the InsP3R modulate hepatic glucose production under fasting conditions and in diabetes.
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a role for the creb co activator CRTC2 in the hypothalamic mechanisms linking glucose sensing with gene regulation
EMBO Reports, 2009Co-Authors: Robin G Lerner, Robert A Screaton, Chantal Depatie, Guy A Rutter, Nina BalthasarAbstract:Within the central nervous system (CNS), the hypothalamus senses and integrates information on the nutrient state of the body. However, the molecular mechanisms translating nutrient sensing into changes in gene expression and, ultimately, nutrient intake remain unclear. A crucial function for the cyclic AMP-response element binding protein (CREB) co-activator CREB-regulated transcription co-activator 2 (CRTC2) in maintaining glucose homeostasis has been shown in the liver. Here, we report CRTC2 expression in distinct areas of the CNS, including hypothalamic neurons. We show that hypothalamic CRTC2 phosphorylation and subcellular localization is altered by nutrient state. Specifically, glucose regulates hypothalamic CRTC2 activity via AMP-activated protein kinase (AMPK)-mediated phosphorylation of CRTC2. Hypothalamic AMPK controls the expression of the cAMP response element (CRE) gene, insulin receptor substrate 2 (Irs2), by regulating CRTC2 occupancy of the Irs2 promoter. Indeed, CRTC2 is required for the appropriate expression of specific hypothalamic CRE genes. Our data identify CRTC2 as a new hypothalamic AMPK target and highlight a role for CRTC2 in the mechanisms linking hypothalamic glucose sensing with CRE gene regulation.
Yiguo Wang - One of the best experts on this subject based on the ideXlab platform.
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the creb coactivator CRTC2 controls hepatic lipid metabolism by regulating srebp1
Nature, 2015Co-Authors: Jinbo Han, Liqun Chen, Yuanyuan Zhang, Fangchao Wei, Jieyuan Liu, Haiteng Deng, Yiguo WangAbstract:Studies in mice reveal that CREB regulated transcription coactivator 2 (CRTC2) acts as a mediator of mTOR signalling in the liver to regulate SREBP1-controlled lipid homeostasis during feeding and diabetes; overexpression of a CRTC2 mutant defective for mTOR regulation improves the lipogenic program and insulin sensitivity in obese mice. SREBP1 is an important transcriptional regulator of lipogenesis. Upon insulin stimulation, it is transported from the endoplasmic reticulum to the Golgi where it is processed, then shuttled to the nucleus to induce genes involved in cholesterol and fatty acid synthesis. From studies in mice, Yiguo Wang and colleagues show that the CREB regulated transcription coactivator 2 (CRTC2) acts as a mediator of mTOR signalling in the liver to regulate SREBP1-controlled lipid homeostasis during feeding and diabetes. CRTC2 can disrupt SREBP1 processing and transport by competing with binding to a subunit of COPII. During feeding, mTOR signalling inhibits the action of CRTC2 on SREBP1 processing. Overexpression of a CRTC2 mutant defective for mTOR regulation improves the lipogenic program and insulin sensitivity in obese mice. Abnormal accumulation of triglycerides in the liver, caused in part by increased de novo lipogenesis, results in non-alcoholic fatty liver disease and insulin resistance1,2. Sterol regulatory element-binding protein 1 (SREBP1), an important transcriptional regulator of lipogenesis, is synthesized as an inactive precursor that binds to the endoplasmic reticulum (ER). In response to insulin signalling, SREBP1 is transported from the ER to the Golgi in a COPII-dependent manner, processed by proteases in the Golgi, and then shuttled to the nucleus to induce lipogenic gene expression3,4,5; however, the mechanisms underlying enhanced SREBP1 activity in insulin-resistant obesity and diabetes remain unclear. Here we show in mice that CREB regulated transcription coactivator 2 (CRTC2)6 functions as a mediator of mTOR7 signalling to modulate COPII-dependent SREBP1 processing. CRTC2 competes with Sec23A, a subunit of the COPII complex8, to interact with Sec31A, another COPII subunit, thus disrupting SREBP1 transport. During feeding, mTOR phosphorylates CRTC2 and attenuates its inhibitory effect on COPII-dependent SREBP1 maturation. As hepatic overexpression of an mTOR-defective CRTC2 mutant in obese mice improved the lipogenic program and insulin sensitivity, these results demonstrate how the transcriptional coactivator CRTC2 regulates mTOR-mediated lipid homeostasis in the fed state and in obesity.
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glucagon creb CRTC2 signaling cascade regulates hepatic bmal1 protein
Journal of Biological Chemistry, 2015Co-Authors: Xiujie Sun, Yiguo Wang, Fabin Dang, Deyi Zhang, Yuan Yuan, Cui Zhang, Yi LiuAbstract:Energy metabolism follows a diurnal pattern responding to the cycles of light and food exposures. Although food availability is a potent synchronizer of peripheral circadian clock in mammals, the underlying mechanism remains elusive. Here, we found that the temporal signals of fasting and refeeding hormones regulate the transcription of Bmal1, a key transcription activator of molecular clock, in the liver. During fasting, glucagon, a major fasting hormone, activates CREB/CRTC2 transcriptional complex that is recruited to Bmal1 promoter to induce its expression. Furthermore, we showed that CRTC2 is required for basal transcriptional regulation of Bmal1 by experiments using either adenovirus-mediated CRTC2 RNAi knockdown or primary CRTC2 null hepatocytes. On the other hand, insulin suppresses fasting-induced Bmal1 expression by inhibiting CRTC2 activity after refeeding. Taken together, our results indicate CRTC2 as a key component of the circadian oscillator that integrates the mammalian clock and energy metabolism.
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inositol 1 4 5 trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes
Nature, 2012Co-Authors: Yiguo Wang, Robert A Screaton, Jason Goode, Jose C Paz, Kunfu Ouyang, Wolfgang H Fischer, Ju Chen, Ira Tabas, Marc MontminyAbstract: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.
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inositol 1 4 5 trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes
Nature, 2012Co-Authors: Yiguo Wang, Robert A Screaton, Jason Goode, Kunfu Ouyang, Wolfgang H Fischer, Ju Chen, Ira Tabas, Gang Li, Marc MontminyAbstract:Interactions between cyclic AMP and calcium signalling pathways mediated by the inositol 1,4,5-trisphosphate receptor are shown to regulate hepatic gluconeogenesis in fasting and diabetes. During fasting, glucose production in the liver is stimulated through an increase in blood glucagon levels, and the cyclic AMP pathway increases gluconeogenic gene expression through activation of the CREB co-activator CRTC2. This study demonstrates interplay between cyclic AMP and calcium signalling pathways, and the participation of inositol-1,4,5-trisphosphate receptors in regulating CRTC2 and hepatic gluconeogenesis under fasting conditions and in diabetes. 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 (InsP3Rs), which associate with CRTC2. After their activation, InsP3Rs 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 InsP3Rs. InsP3R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic downregulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrate how interactions between cAMP and calcium pathways at the level of the InsP3R modulate hepatic glucose production under fasting conditions and in diabetes.
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targeted disruption of the creb coactivator CRTC2 increases insulin sensitivity
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Yiguo Wang, Hiroshi Inoue, Yi Liu, Susan Hedrick, Kim Ravnskjaer, Kristin Viste, Nina Miller, Liliana Vera, Marc MontminyAbstract: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.
Seung Hoi Koo - One of the best experts on this subject based on the ideXlab platform.
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role of CRTC2 in metabolic homeostasis key regulator of whole body energy metabolism
Diabetes & Metabolism Journal, 2020Co-Authors: Hye Sook Han, Yongmin Kwon, Seung Hoi KooAbstract:Cyclic adenosine monophosphate (cAMP) signaling is critical for regulating metabolic homeostasis in mammals. In particular, transcriptional regulation by cAMP response element-binding protein (CREB) and its coactivator, CREB-regulated transcription coactivator (CRTC), is essential for controlling the expression of critical enzymes in the metabolic process, leading to more chronic changes in metabolic flux. Among the CRTC isoforms, CRTC2 is predominantly expressed in peripheral tissues and has been shown to be associated with various metabolic pathways in tissue-specific manners. While initial reports showed the physiological role of CRTC2 in regulating gluconeogenesis in the liver, recent studies have further delineated the role of this transcriptional coactivator in the regulation of glucose and lipid metabolism in various tissues, including the liver, pancreatic islets, endocrine tissues of the small intestines, and adipose tissues. In this review, we discuss recent studies that have utilized knockout mouse models to delineate the role of CRTC2 in the regulation of metabolic homeostasis.
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hepatic CRTC2 controls whole body energy metabolism via a mir 34a fgf21 axis
Nature Communications, 2017Co-Authors: Hye Sook Han, Byeong Hun Choi, Jun Seok Kim, Geon Kang, Seung Hoi KooAbstract:Liver plays a crucial role in controlling energy homeostasis in mammals, although the exact mechanism by which it influences other peripheral tissues has yet to be addressed. Here we show that Creb regulates transcriptional co-activator (Crtc) 2 is a major regulator of whole-body energy metabolism. CRTC2 liver-specific knockout lowers blood glucose levels with improved glucose and insulin tolerance. Liver-specific knockout mice display increased energy expenditure with smaller lipid droplets in adipose depots. Both plasma and hepatic Fgf21 levels are increased in CRTC2 liver-specific knockout mice, as a result of the reduced miR-34a expression regulated by Creb/CRTC2 and the induction of Sirt1 and Pparα. Ectopic expression of miR-34a reverses the metabolic changes in knockout liver. We suggest that Creb/CRTC2 negatively regulates the Sirt1/Pparα/Fgf21 axis via the induction of miR-34a under diet-induced obesity and insulin-resistant conditions. CREB-regulated transcription coactivator 2, CRTC2, has been associated with regulation of glucose and lipid homeostasis. Here Han et al. show that Creb/CRTC2 modulates lipid and glucose metabolism by inhibiting the expression of mi-R34 that, in turn, represses the expression of Sirt1 and PPARα and consequently Fgf21 levels.
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Hepatic CRTC2 controls whole body energy metabolism via a miR-34a-Fgf21 axis
Nature Publishing Group, 2017Co-Authors: Hye Sook Han, Byeong Hun Choi, Jun Seok Kim, Geon Kang, Seung Hoi KooAbstract:CREB-regulated transcription coactivator 2, CRTC2, has been associated with regulation of glucose and lipid homeostasis. Here Han et al. show that Creb/CRTC2 modulates lipid and glucose metabolism by inhibiting the expression of mi-R34 that, in turn, represses the expression of Sirt1 and PPARα and consequently Fgf21 levels
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arginine methylation of CRTC2 is critical in the transcriptional control of hepatic glucose metabolism
Science Signaling, 2014Co-Authors: Hye Sook Han, Young-sil Yoon, Geon Kang, Dahee Choi, Chang Yun Jung, Seri Choi, Keungyu Park, Seongtae Kim, Seung Hoi KooAbstract:Fasting glucose homeostasis is maintained in part through cAMP (adenosine 3′,5′-monophosphate)– dependent transcriptional control of hepatic gluconeogenesis by the transcription factor CREB (cAMP response element–binding protein) and its coactivator CRTC2 (CREB-regulated transcriptional coactivator 2). We showed that PRMT6 (protein arginine methyltransferase 6) promotes fasting-induced transcriptional activation of the gluconeogenic program involving CRTC2. Mass spectrometric analysis indicated that PRMT6 associated with CRTC2. In cells, PRMT6 mediated asymmetric dimethylation of multiple arginine residues of CRTC2, which enhanced the association of CRTC2 with CREB on the promoters of gluconeogenic enzyme–encoding genes. In mice, ectopic expression of PRMT6 promoted higher blood glucose concentrations, which were associated with increased expression of genes encoding gluconeogenic factors, whereas knockdown of hepatic PRMT6 decreased fasting glycemia and improved pyruvate tolerance. The abundance of hepatic PRMT6 was increased in mouse models of obesity and insulin resistance, and adenovirus-mediated depletion of PRMT6 restored euglycemia in these mice. We propose that PRMT6 is involved in the regulation of hepatic glucose metabolism in a CRTC2-dependent manner.
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Adiponectin and thiazolidinedione targets CRTC2 to regulate hepatic gluconeogenesis
Experimental & Molecular Medicine, 2009Co-Authors: Young-sil Yoon, Dongryeol Ryu, Min-woo Lee, Sungpyo Hong, Seung Hoi KooAbstract:During fasting periods, hepatic glucose production is enhanced by glucagon to provide fuels for other organs. This process is mediated via cAMP-dependent induction of the CREB regulated transcriptional coactivator (CRTC) 2, a critical transcriptional activator for hepatic gluconeogenesis. We have previously shown that CRTC2 activity is regulated by AMP activated protein kinase (AMPK) family members. Here we show that adiponectin and thiazolidinedione directly regulate AMPK to modulate CRTC2 activity in hepatocytes. Adiponectin or thiazolidinedione lowered glucose production from primary hepatocytes. Treatment of both reagents reduced gluconeogenic gene expression as well as cAMP-mediated induction of CRE reporter, suggesting that these reagents directly affect CREB/CRTC2- dependent transcription. Furthermore, adiponectin or thiazolidinedione mediated repression of CRE activity is largely blunted by co-expression of phosphorylation defective mutant CRTC2, underscoring the importance of serine 171 residue of this factor. Taken together, we propose that adiponectin and thiazolidinedione promote the modulation of AMPK-dependent CRTC2 activity to influence hepatic gluconeogenesis.
Hye Sook Han - One of the best experts on this subject based on the ideXlab platform.
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a novel role of CRTC2 in promoting nonalcoholic fatty liver disease
Molecular metabolism, 2021Co-Authors: Hye Sook Han, Yongmin Kwon, Sang Gyune Kim, Young Seok Kim, Sihyong Jang, Dahee Choi, Tom Huh, Eunyoung Moon, Eunyong Ahn, Je Kyung SeongAbstract:Abstract Objective Diet-induced obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which instigates severe metabolic disorders including cirrhosis, hepatocellular carcinoma and type 2 diabetes. Recently, we have shown that hepatic depletion of CREB regulated transcription co-activator (CRTC) 2 protects mice from the progression of diet-induced fatty liver phenotype, although the exact mechanism by which CRTC2 modulates this process is elusive to date. Here we investigated the role of hepatic CRTC2 in the instigation of NAFLD in mammals. Methods CRTC2 liver-specific knockout (CRTC2 LKO) mice and CRTC2 flox/flox (CRTC2 f/f) mice were fed high fat diet (HFD) for 7-8 weeks. Body weight, liver weight, hepatic lipid contents, and plasma triacylglycerol (TG) levels were determined. Western blot analysis was performed to determine Sirtuin (SIRT) 1, tuberous sclerosis complex (TSC) 2, and mammalian target of rapamycin complex (mTORC) 1 activity in the liver. Effects of CRTC2 depletion on lipogenesis was determined by measurement of lipogenic gene expression (western blot analysis and qRT-PCR) in the liver as well as oil red o staining in hepatocytes. Effects of miR-34a on mTORC1 activity and hepatic lipid accumulation was assessed by AAV-miR-34a virus in mice and Ad-miR-34a virus and Ad-anti-miR-34a virus in hepatocytes. Autophagic flux was assessed by western blot analysis after leupeptin injection in mice and bafilomycin treatment in hepatocytes. Lipophagy was assessed by transmission electron microscopy and confocal microscopy. Expression of CRTC2 and p-S6K1 in livers of human NAFLD patients were assessed by immunohisotochemistry. Results We found that expression of CRTC2 in the liver is highly induced upon HFD-feeding in mice. Hepatic depletion of CRTC2 ameliorated HFD-induced fatty liver disease phenotypes, with a pronounced inhibition of mTORC1 pathway in the liver. Mechanistically, we found that expression of TSC2, a potent mTORC1 inhibitor, was enhanced in CRTC2 LKO mice, due to the decreased expression of miR-34a and the subsequent increase in SIRT1-mediated deacetylation processes. Indeed, we showed that ectopic expression of miR-34a led to the induction of mTORC1 pathway, leading to the hepatic lipid accumulation in part by limiting lipophagy and enhanced lipogenesis. Finally, we found a strong association of CRTC2, miR-34a and mTORC1 activity in the NAFLD patients in humans, demonstrating a conservation of signaling pathways among species. Conclusions These data collectively suggest that diet-induced activation of CRTC2 instigates the progression of NAFLD by activating miR-34a-mediated lipid accumulation in the liver via the simultaneous induction of lipogenesis and inhibition of lipid catabolism. Therapeutic approach to specifically inhibit CRTC2 activity in the liver could be beneficial in combating NAFLD in the future.
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role of CRTC2 in metabolic homeostasis key regulator of whole body energy metabolism
Diabetes & Metabolism Journal, 2020Co-Authors: Hye Sook Han, Yongmin Kwon, Seung Hoi KooAbstract:Cyclic adenosine monophosphate (cAMP) signaling is critical for regulating metabolic homeostasis in mammals. In particular, transcriptional regulation by cAMP response element-binding protein (CREB) and its coactivator, CREB-regulated transcription coactivator (CRTC), is essential for controlling the expression of critical enzymes in the metabolic process, leading to more chronic changes in metabolic flux. Among the CRTC isoforms, CRTC2 is predominantly expressed in peripheral tissues and has been shown to be associated with various metabolic pathways in tissue-specific manners. While initial reports showed the physiological role of CRTC2 in regulating gluconeogenesis in the liver, recent studies have further delineated the role of this transcriptional coactivator in the regulation of glucose and lipid metabolism in various tissues, including the liver, pancreatic islets, endocrine tissues of the small intestines, and adipose tissues. In this review, we discuss recent studies that have utilized knockout mouse models to delineate the role of CRTC2 in the regulation of metabolic homeostasis.
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hepatic CRTC2 controls whole body energy metabolism via a mir 34a fgf21 axis
Nature Communications, 2017Co-Authors: Hye Sook Han, Byeong Hun Choi, Jun Seok Kim, Geon Kang, Seung Hoi KooAbstract:Liver plays a crucial role in controlling energy homeostasis in mammals, although the exact mechanism by which it influences other peripheral tissues has yet to be addressed. Here we show that Creb regulates transcriptional co-activator (Crtc) 2 is a major regulator of whole-body energy metabolism. CRTC2 liver-specific knockout lowers blood glucose levels with improved glucose and insulin tolerance. Liver-specific knockout mice display increased energy expenditure with smaller lipid droplets in adipose depots. Both plasma and hepatic Fgf21 levels are increased in CRTC2 liver-specific knockout mice, as a result of the reduced miR-34a expression regulated by Creb/CRTC2 and the induction of Sirt1 and Pparα. Ectopic expression of miR-34a reverses the metabolic changes in knockout liver. We suggest that Creb/CRTC2 negatively regulates the Sirt1/Pparα/Fgf21 axis via the induction of miR-34a under diet-induced obesity and insulin-resistant conditions. CREB-regulated transcription coactivator 2, CRTC2, has been associated with regulation of glucose and lipid homeostasis. Here Han et al. show that Creb/CRTC2 modulates lipid and glucose metabolism by inhibiting the expression of mi-R34 that, in turn, represses the expression of Sirt1 and PPARα and consequently Fgf21 levels.
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Hepatic CRTC2 controls whole body energy metabolism via a miR-34a-Fgf21 axis
Nature Publishing Group, 2017Co-Authors: Hye Sook Han, Byeong Hun Choi, Jun Seok Kim, Geon Kang, Seung Hoi KooAbstract:CREB-regulated transcription coactivator 2, CRTC2, has been associated with regulation of glucose and lipid homeostasis. Here Han et al. show that Creb/CRTC2 modulates lipid and glucose metabolism by inhibiting the expression of mi-R34 that, in turn, represses the expression of Sirt1 and PPARα and consequently Fgf21 levels
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arginine methylation of CRTC2 is critical in the transcriptional control of hepatic glucose metabolism
Science Signaling, 2014Co-Authors: Hye Sook Han, Young-sil Yoon, Geon Kang, Dahee Choi, Chang Yun Jung, Seri Choi, Keungyu Park, Seongtae Kim, Seung Hoi KooAbstract:Fasting glucose homeostasis is maintained in part through cAMP (adenosine 3′,5′-monophosphate)– dependent transcriptional control of hepatic gluconeogenesis by the transcription factor CREB (cAMP response element–binding protein) and its coactivator CRTC2 (CREB-regulated transcriptional coactivator 2). We showed that PRMT6 (protein arginine methyltransferase 6) promotes fasting-induced transcriptional activation of the gluconeogenic program involving CRTC2. Mass spectrometric analysis indicated that PRMT6 associated with CRTC2. In cells, PRMT6 mediated asymmetric dimethylation of multiple arginine residues of CRTC2, which enhanced the association of CRTC2 with CREB on the promoters of gluconeogenic enzyme–encoding genes. In mice, ectopic expression of PRMT6 promoted higher blood glucose concentrations, which were associated with increased expression of genes encoding gluconeogenic factors, whereas knockdown of hepatic PRMT6 decreased fasting glycemia and improved pyruvate tolerance. The abundance of hepatic PRMT6 was increased in mouse models of obesity and insulin resistance, and adenovirus-mediated depletion of PRMT6 restored euglycemia in these mice. We propose that PRMT6 is involved in the regulation of hepatic glucose metabolism in a CRTC2-dependent manner.