The Experts below are selected from a list of 288 Experts worldwide ranked by ideXlab platform
Shannon M. Reilly - One of the best experts on this subject based on the ideXlab platform.
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a subcutaneous adipose tissue liver signalling axis controls hepatic gluconeogenesis
Nature Communications, 2015Co-Authors: Shannon M. Reilly, Louise Chang, Maryam Ahmadian, Brian F Zamarron, Breanne Poirier, Xiaoling Peng, Danielle M Krause, Evgenia Korytnaya, Adam Neidert, Christopher LiddleAbstract:The drug Amlexanox is known to improve obesity-related metabolic dysfunction in mice. Here the authors show that this effect is mediated by interleukin-6 secreted from subcutaneous adipocytes, which then inhibits gluconeogenesis in the liver by phosphorylating the hepatic transcription factor Stat3.
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a subcutaneous adipose tissue liver signalling axis controls hepatic gluconeogenesis
Nature Communications, 2015Co-Authors: Shannon M. Reilly, Louise Chang, Maeran Uhm, Maryam Ahmadian, Brian F Zamarron, Breanne Poirier, Xiaoling Peng, Danielle M Krause, Evgenia Korytnaya, Adam NeidertAbstract:The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-e and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-e and TBK1 with Amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of Amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes.
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inflammation produces catecholamine resistance in obesity via activation of pde3b by the protein kinases ikke and tbk1
eLife, 2013Co-Authors: Jonathan Mowers, Shannon M. Reilly, Shian Huey Chiang, Louise Chang, Maeran Uhm, Joshua Simon, Dara Leto, Alan R SaltielAbstract:Obesity produces a chronic inflammatory state involving the NFκB pathway, resulting in persistent elevation of the noncanonical IκB kinases IKKe and TBK1. In this study, we report that these kinases attenuate β-adrenergic signaling in white adipose tissue. Treatment of 3T3-L1 adipocytes with specific inhibitors of these kinases restored β-adrenergic signaling and lipolysis attenuated by TNFα and Poly (I:C). Conversely, overexpression of the kinases reduced induction of Ucp1, lipolysis, cAMP levels, and phosphorylation of hormone sensitive lipase in response to isoproterenol or forskolin. Noncanonical IKKs reduce catecholamine sensitivity by phosphorylating and activating the major adipocyte phosphodiesterase PDE3B. In vivo inhibition of these kinases by treatment of obese mice with the drug Amlexanox reversed obesity-induced catecholamine resistance, and restored PKA signaling in response to injection of a β-3 adrenergic agonist. These studies suggest that by reducing production of cAMP in adipocytes, IKKe and TBK1 may contribute to the repression of energy expenditure during obesity. DOI: http://dx.doi.org/10.7554/eLife.01119.001.
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An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice
Nature medicine, 2013Co-Authors: Shannon M. Reilly, Shian Huey Chiang, Stuart J. Decker, Louise Chang, Maeran Uhm, Martha J. Larsen, John R. Rubin, Jonathan Mowers, Nicole M.a. White, Irit HochbergAbstract:Alan Saltiel and his colleagues report that the approved drug Amlexanox, currently used to treat asthma and canker sores, is a relatively specific inhibitor of the noncanonical IκB kinases IKK-ɛ and TANK-binding kinase 1 (TBK1) and that it improves metabolic disease in mouse genetic and dietary models of obesity. These results suggest this drug may be repurposed to treat obesity and insulin resistance.
Louise Chang - One of the best experts on this subject based on the ideXlab platform.
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a subcutaneous adipose tissue liver signalling axis controls hepatic gluconeogenesis
Nature Communications, 2015Co-Authors: Shannon M. Reilly, Louise Chang, Maryam Ahmadian, Brian F Zamarron, Breanne Poirier, Xiaoling Peng, Danielle M Krause, Evgenia Korytnaya, Adam Neidert, Christopher LiddleAbstract:The drug Amlexanox is known to improve obesity-related metabolic dysfunction in mice. Here the authors show that this effect is mediated by interleukin-6 secreted from subcutaneous adipocytes, which then inhibits gluconeogenesis in the liver by phosphorylating the hepatic transcription factor Stat3.
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a subcutaneous adipose tissue liver signalling axis controls hepatic gluconeogenesis
Nature Communications, 2015Co-Authors: Shannon M. Reilly, Louise Chang, Maeran Uhm, Maryam Ahmadian, Brian F Zamarron, Breanne Poirier, Xiaoling Peng, Danielle M Krause, Evgenia Korytnaya, Adam NeidertAbstract:The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-e and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-e and TBK1 with Amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of Amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes.
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inflammation produces catecholamine resistance in obesity via activation of pde3b by the protein kinases ikke and tbk1
eLife, 2013Co-Authors: Jonathan Mowers, Shannon M. Reilly, Shian Huey Chiang, Louise Chang, Maeran Uhm, Joshua Simon, Dara Leto, Alan R SaltielAbstract:Obesity produces a chronic inflammatory state involving the NFκB pathway, resulting in persistent elevation of the noncanonical IκB kinases IKKe and TBK1. In this study, we report that these kinases attenuate β-adrenergic signaling in white adipose tissue. Treatment of 3T3-L1 adipocytes with specific inhibitors of these kinases restored β-adrenergic signaling and lipolysis attenuated by TNFα and Poly (I:C). Conversely, overexpression of the kinases reduced induction of Ucp1, lipolysis, cAMP levels, and phosphorylation of hormone sensitive lipase in response to isoproterenol or forskolin. Noncanonical IKKs reduce catecholamine sensitivity by phosphorylating and activating the major adipocyte phosphodiesterase PDE3B. In vivo inhibition of these kinases by treatment of obese mice with the drug Amlexanox reversed obesity-induced catecholamine resistance, and restored PKA signaling in response to injection of a β-3 adrenergic agonist. These studies suggest that by reducing production of cAMP in adipocytes, IKKe and TBK1 may contribute to the repression of energy expenditure during obesity. DOI: http://dx.doi.org/10.7554/eLife.01119.001.
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An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice
Nature medicine, 2013Co-Authors: Shannon M. Reilly, Shian Huey Chiang, Stuart J. Decker, Louise Chang, Maeran Uhm, Martha J. Larsen, John R. Rubin, Jonathan Mowers, Nicole M.a. White, Irit HochbergAbstract:Alan Saltiel and his colleagues report that the approved drug Amlexanox, currently used to treat asthma and canker sores, is a relatively specific inhibitor of the noncanonical IκB kinases IKK-ɛ and TANK-binding kinase 1 (TBK1) and that it improves metabolic disease in mouse genetic and dietary models of obesity. These results suggest this drug may be repurposed to treat obesity and insulin resistance.
Adam Neidert - One of the best experts on this subject based on the ideXlab platform.
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a subcutaneous adipose tissue liver signalling axis controls hepatic gluconeogenesis
Nature Communications, 2015Co-Authors: Shannon M. Reilly, Louise Chang, Maeran Uhm, Maryam Ahmadian, Brian F Zamarron, Breanne Poirier, Xiaoling Peng, Danielle M Krause, Evgenia Korytnaya, Adam NeidertAbstract:The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-e and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-e and TBK1 with Amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of Amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes.
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a subcutaneous adipose tissue liver signalling axis controls hepatic gluconeogenesis
Nature Communications, 2015Co-Authors: Shannon M. Reilly, Louise Chang, Maryam Ahmadian, Brian F Zamarron, Breanne Poirier, Xiaoling Peng, Danielle M Krause, Evgenia Korytnaya, Adam Neidert, Christopher LiddleAbstract:The drug Amlexanox is known to improve obesity-related metabolic dysfunction in mice. Here the authors show that this effect is mediated by interleukin-6 secreted from subcutaneous adipocytes, which then inhibits gluconeogenesis in the liver by phosphorylating the hepatic transcription factor Stat3.
Robert B Bentham - One of the best experts on this subject based on the ideXlab platform.
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macrophages induce malignant traits in mammary epithelium via ikke tbk1 kinases and the serine biosynthesis pathway
Embo Molecular Medicine, 2020Co-Authors: Ewa Wilczvillega, Edward P Carter, Alastair Ironside, Isabella Mataloni, Julie Holdsworth, William Jones, Rocio Moreno Bejar, Lukas Uhlik, Robert B Bentham, Susana A GodinhoAbstract:During obesity, macrophages infiltrate the breast tissue leading to low-grade chronic inflammation, a factor considered responsible for the higher risk of breast cancer associated with obesity. Here, we formally demonstrate that breast epithelial cells acquire malignant properties when exposed to medium conditioned by macrophages derived from human healthy donors. These effects were mediated by the breast cancer oncogene IKKe and its downstream target-the serine biosynthesis pathway as demonstrated by genetic or pharmacological tools. Furthermore, Amlexanox, an FDA-approved drug targeting IKKe and its homologue TBK1, delayed in vivo tumour formation in a combined genetic mouse model of breast cancer and high-fat diet-induced obesity/inflammation. Finally, in human breast cancer tissues, we validated the link between inflammation-IKKe and alteration of cellular metabolism. Altogether, we identified a pathway connecting obesity-driven inflammation to breast cancer and a potential therapeutic strategy to reduce the risk of breast cancer associated with obesity.
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Macrophages induce malignant traits in mammary epithelium via IKK epsilon/TBK1 kinases and the serine biosynthesis pathway
'Royal College of Obstetricians & Gynaecologists (RCOG)', 2020Co-Authors: Wilcz-villega E, Carter E, Ironside A, Holdsworth J, Jones W, Rm Bejar, Uhlik L, Robert B BenthamAbstract:During obesity, macrophages infiltrate the breast tissue leading to low-grade chronic inflammation, a factor considered responsible for the higher risk of breast cancer associated with obesity. Here, we formally demonstrate that breast epithelial cells acquire malignant properties when exposed to medium conditioned by macrophages derived from human healthy donors. These effects were mediated by the breast cancer oncogene IKK epsilon and its downstream target-the serine biosynthesis pathway as demonstrated by genetic or pharmacological tools. Furthermore, Amlexanox, an FDA-approved drug targeting IKK epsilon and its homologue TBK1, delayed in vivo tumour formation in a combined genetic mouse model of breast cancer and high-fat diet-induced obesity/inflammation. Finally, in human breast cancer tissues, we validated the link between inflammation-IKK epsilon and alteration of cellular metabolism. Altogether, we identified a pathway connecting obesity-driven inflammation to breast cancer and a potential therapeutic strategy to reduce the risk of breast cancer associated with obesity
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Macrophages induce malignant traits in mammary epithelium via IKKε/TBK1 kinases and the serine biosynthesis pathway
'EMBO', 2020Co-Authors: Ewa Wilcz‐villega, Alastair Ironside, Isabella Mataloni, Julie Holdsworth, William Jones, Rocio Moreno Bejar, Lukas Uhlik, Edward Carter, Robert B BenthamAbstract:Abstract During obesity, macrophages infiltrate the breast tissue leading to low‐grade chronic inflammation, a factor considered responsible for the higher risk of breast cancer associated with obesity. Here, we formally demonstrate that breast epithelial cells acquire malignant properties when exposed to medium conditioned by macrophages derived from human healthy donors. These effects were mediated by the breast cancer oncogene IKKε and its downstream target—the serine biosynthesis pathway as demonstrated by genetic or pharmacological tools. Furthermore, Amlexanox, an FDA‐approved drug targeting IKKε and its homologue TBK1, delayed in vivo tumour formation in a combined genetic mouse model of breast cancer and high‐fat diet‐induced obesity/inflammation. Finally, in human breast cancer tissues, we validated the link between inflammation–IKKε and alteration of cellular metabolism. Altogether, we identified a pathway connecting obesity‐driven inflammation to breast cancer and a potential therapeutic strategy to reduce the risk of breast cancer associated with obesity
Byung Ho Lee - One of the best experts on this subject based on the ideXlab platform.
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A novel role of G protein-coupled receptor kinase 5 in urotensin II-stimulated cellular hypertrophy in H9c2_UT cells
Molecular and Cellular Biochemistry, 2016Co-Authors: Cheon Ho Park, Ju Hee Lee, Mi Young Lee, Jeong Hyun Lee, Byung Ho LeeAbstract:Urotensin II (UII) is a neural hormone that induces cardiac hypertrophy and may be involved in the pathogenesis of cardiac remodeling and heart failure. Hypertrophy has been linked to histone deacetylase 5 (HDAC5) phosphorylation and nuclear factor κB (NF-κB) translocation, both of which are predominantly mediated by G protein-coupled receptor kinase 5 (GRK5). In the present study, we found that UII rapidly and strongly stimulated nuclear export of HDAC5 and nuclear import of NF-κB in H9c2 cells overexpressing the urotensin II receptor (H9c2_UT). Hence, we hypothesized that GRK5 and its signaling pathway may play a role in UII-mediated cellular hypertrophy. H9c2_UT cells were transduced with a GRK5 small hairpin RNA interference recombinant lentivirus, resulting in the down-regulation of GRK5. Under UII stimulation, reduced levels of GRK5 in H9c2_UT cells led to suppression of UII-mediated HDAC5 phosphorylation and activation of the NF-κB signaling pathway. In contrast, UII-mediated activations of ERK1/2 and GSK3α/β were not affected by down-regulation of GRK5. In a cellular hypertrophy assay, down-regulation of GRK5 significantly suppressed UII-mediated hypertrophy of H9c2_UT cells. Furthermore, UII-mediated cellular hypertrophy was inhibited by Amlexanox, a selective GRK5 inhibitor, in H9c2_UT cells and neonatal cardiomyocytes. Our results suggest that GRK5 may be involved in a UII-mediated hypertrophic response via activation of NF-κB and HDAC5 at least in part by ERK1/2 and GSK3α/β-independent pathways.