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Articles 1 - 8 of 8

Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Tenomodulin Promotes Human Adipocyte Differentiation And Beneficial Visceral Adipose Tissue Expansion, Ozlem Senol-Cosar, Rachel J. Roth Flach, Marina Distefano, Anil K. Chawla, Sarah M. Nicoloro, Juerg R. Straubhaar, Olga T. Hardy, Hye Lim Noh, Jason K. Kim, Martin Wabitsch, Philipp E. Scherer, Michael P. Czech Feb 2016

Tenomodulin Promotes Human Adipocyte Differentiation And Beneficial Visceral Adipose Tissue Expansion, Ozlem Senol-Cosar, Rachel J. Roth Flach, Marina Distefano, Anil K. Chawla, Sarah M. Nicoloro, Juerg R. Straubhaar, Olga T. Hardy, Hye Lim Noh, Jason K. Kim, Martin Wabitsch, Philipp E. Scherer, Michael P. Czech

Program in Molecular Medicine Publications and Presentations

Proper regulation of energy storage in adipose tissue is crucial for maintaining insulin sensitivity and molecules contributing to this process have not been fully revealed. Here we show that type II transmembrane protein tenomodulin (TNMD) is upregulated in adipose tissue of insulin-resistant versus insulin-sensitive individuals, who were matched for body mass index (BMI). TNMD expression increases in human preadipocytes during differentiation, whereas silencing TNMD blocks adipogenesis. Upon high-fat diet feeding, transgenic mice overexpressing Tnmd develop increased epididymal white adipose tissue (eWAT) mass, and preadipocytes derived from Tnmd transgenic mice display greater proliferation, consistent with elevated adipogenesis. In Tnmd transgenic mice ...


Endothelial Protein Kinase Map4k4 Promotes Vascular Inflammation And Atherosclerosis, Rachel J. Roth Flach, Athanasia Skoura, Anouch Matevossian, Laura V. Danai, Wei Zheng, Christian Cortes, Samit K. Bhattacharya, Myriam Aouadi, G. Nana Hagan, Joseph Yawe, Pranitha Vangala, Lorena Garcia Menendez, Marcus P. Cooper, Timothy P. Fitzgibbons, Leonard Buckbinder, Michael P. Czech Dec 2015

Endothelial Protein Kinase Map4k4 Promotes Vascular Inflammation And Atherosclerosis, Rachel J. Roth Flach, Athanasia Skoura, Anouch Matevossian, Laura V. Danai, Wei Zheng, Christian Cortes, Samit K. Bhattacharya, Myriam Aouadi, G. Nana Hagan, Joseph Yawe, Pranitha Vangala, Lorena Garcia Menendez, Marcus P. Cooper, Timothy P. Fitzgibbons, Leonard Buckbinder, Michael P. Czech

Program in Molecular Medicine Publications and Presentations

Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe(-/-) mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe(-/-) and Ldlr(-/-) mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic ...


Inducible Deletion Of Protein Kinase Map4k4 In Obese Mice Improves Insulin Sensitivity In Liver And Adipose Tissues, Laura V. Danai, Rachel J. Roth Flach, Joseph V Virbasius, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Jason K. Kim, Michael P. Czech Jul 2015

Inducible Deletion Of Protein Kinase Map4k4 In Obese Mice Improves Insulin Sensitivity In Liver And Adipose Tissues, Laura V. Danai, Rachel J. Roth Flach, Joseph V Virbasius, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Jason K. Kim, Michael P. Czech

Program in Molecular Medicine Publications and Presentations

Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) attenuates insulin signaling, but confirmation in vivo is lacking since Map4k4 knockout is lethal during embryogenesis. We thus generated mice with floxed Map4k4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body Map4k4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced Map4k4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with ...


Highly Selective In Vivo Labeling Of Subcutaneous White Adipocyte Precursors With Prx1-Cre, Joan Sanchez-Gurmaches, Wen-Yu Hsiao, David A. Guertin Apr 2015

Highly Selective In Vivo Labeling Of Subcutaneous White Adipocyte Precursors With Prx1-Cre, Joan Sanchez-Gurmaches, Wen-Yu Hsiao, David A. Guertin

Program in Molecular Medicine Publications and Presentations

The origins of individual fat depots are not well understood, and thus, the availability of tools useful for studying depot-specific adipose tissue development and function is limited. Cre drivers that selectively target only brown adipocyte, subcutaneous white adipocyte, or visceral white adipocyte precursors would have significant value because they could be used to selectively study individual depots without impacting the adipocyte precursors or intrinsic metabolic properties of the other depots. Here, we show that the majority of the precursor and mature subcutaneous white adipocytes in adult C57Bl/6 mice are labeled by Prx1-Cre. In sharp contrast, few to no brown ...


Hdac6 Regulates Tip60-P400 Function In Stem Cells, Poshen B. Chen, Jui-Hung Hung, Taylor L. Hickman, Andrew H. Coles, James F. Carey, Zhiping Weng, Feixia Chu, Thomas G. Fazzio Dec 2013

Hdac6 Regulates Tip60-P400 Function In Stem Cells, Poshen B. Chen, Jui-Hung Hung, Taylor L. Hickman, Andrew H. Coles, James F. Carey, Zhiping Weng, Feixia Chu, Thomas G. Fazzio

Program in Molecular Medicine Publications and Presentations

In embryonic stem cells (ESCs), the Tip60 histone acetyltransferase activates genes required for proliferation and silences genes that promote differentiation. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs. Hdac6 is necessary for regulation of most Tip60-p400 target genes, particularly those repressed by the complex. Unlike differentiated cells, where Hdac6 is mainly cytoplasmic, Hdac6 is largely nuclear in ESCs, neural stem cells (NSCs), and some cancer cell lines, and interacts with Tip60-p400 in each. Hdac6 localizes to promoters bound by Tip60-p400 in ESCs, binding downstream of transcription start sites. Surprisingly, Hdac6 does not ...


Diet-Induced Obesity Mediated By The Jnk/Dio2 Signal Transduction Pathway, Santiago Vernia, Julie Cavanagh-Kyros, Tamera Barrett, Dae Young Jung, Jason K. Kim, Roger J. Davis Nov 2013

Diet-Induced Obesity Mediated By The Jnk/Dio2 Signal Transduction Pathway, Santiago Vernia, Julie Cavanagh-Kyros, Tamera Barrett, Dae Young Jung, Jason K. Kim, Roger J. Davis

Program in Molecular Medicine Publications and Presentations

The cJun N-terminal kinase (JNK) signaling pathway is a key mediator of metabolic stress responses caused by consuming a high-fat diet, including the development of obesity. To test the role of JNK, we examined diet-induced obesity in mice with targeted ablation of Jnk genes in the anterior pituitary gland. These mice exhibited an increase in the pituitary expression of thyroid-stimulating hormone (TSH), an increase in the blood concentration of thyroid hormone (T4), increased energy expenditure, and markedly reduced obesity compared with control mice. The increased amount of pituitary TSH was caused by reduced expression of type 2 iodothyronine deiodinase (Dio2 ...


Inductive Asymmetric Cell Division: The Wrm Leads The Way, Takao Ishidate, Soyoung Kim, Craig C. Mello, Masaki Shirayama Oct 2013

Inductive Asymmetric Cell Division: The Wrm Leads The Way, Takao Ishidate, Soyoung Kim, Craig C. Mello, Masaki Shirayama

Program in Molecular Medicine Publications and Presentations

C. elegans, with its invariant cell lineage, provides a powerful model system in which to study signaling-dependent asymmetric cell division. The C. elegans β-catenin-related protein, WRM-1, specifies endoderm at the 4-cell stage during the first cell signaling-induced asymmetric cell division of embryogenesis. During this interaction, Wnt signaling and the cell cycle regulator CDK-1 act together to induce the asymmetric cortical release of WRM-1 at prophase of the EMS cell cycle. Genetic studies suggest that release of WRM-1 unmasks a cortical site that drives EMS spindle rotation onto the polarized axis of the cell, simultaneously making WRM-1 available for nuclear translocation ...


Role Of The Mixed-Lineage Protein Kinase Pathway In The Metabolic Stress Response To Obesity, Shashi Kant, Tamera Barrett, Anastassiia Vertii, Yun Hee Noh, Dae Young Jung, Jason K. Kim, Roger J. Davis Aug 2013

Role Of The Mixed-Lineage Protein Kinase Pathway In The Metabolic Stress Response To Obesity, Shashi Kant, Tamera Barrett, Anastassiia Vertii, Yun Hee Noh, Dae Young Jung, Jason K. Kim, Roger J. Davis

Program in Molecular Medicine Publications and Presentations

Saturated free fatty acid (FFA) is implicated in the metabolic response to obesity. In vitro studies indicate that FFA signaling may be mediated by the mixed-lineage protein kinase (MLK) pathway that activates cJun NH2-terminal kinase (JNK). Here, we examined the role of the MLK pathway in vivo using a mouse model of diet-induced obesity. The ubiquitously expressed MLK2 and MLK3 protein kinases have partially redundant functions. We therefore compared wild-type and compound mutant mice that lack expression of MLK2 and MLK3. MLK deficiency protected mice against high-fat-diet-induced insulin resistance and obesity. Reduced JNK activation and increased energy expenditure contribute to ...