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Full-Text Articles in Life Sciences

Coronary Disease Is Not Associated With Robust Alterations In Inflammatory Gene Expression In Human Epicardial Fat, Timothy P. Fitzgibbons, Nancy Lee, Khanh-Van T. Tran, Sarah M. Nicoloro, Mark Kelly, Stanley Kc Tam, Michael P. Czech Oct 2019

Coronary Disease Is Not Associated With Robust Alterations In Inflammatory Gene Expression In Human Epicardial Fat, Timothy P. Fitzgibbons, Nancy Lee, Khanh-Van T. Tran, Sarah M. Nicoloro, Mark Kelly, Stanley Kc Tam, Michael P. Czech

Open Access Articles

Epicardial adipose tissue (EAT) is the visceral fat depot of the heart. Inflammation of EAT is thought to contribute to coronary artery disease (CAD). Therefore, we hypothesized that the EAT of patients with CAD would have increased inflammatory gene expression compared with controls without CAD. Cardiac surgery patients with (n = 13) or without CAD (n = 13) were consented, and samples of EAT and subcutaneous adipose tissue (SAT) were obtained. Transcriptomic analysis was performed using Affymetrix Human Gene 1.0 ST arrays. Differential expression was defined as a 1.5-fold change (ANOVA P < 0.05). Six hundred ninety-three genes were differentially expressed between SAT and EAT in controls and 805 in cases. Expression of 326 genes was different between EAT of cases and controls; expression of 14 genes was increased in cases, while 312 were increased in controls. Quantitative reverse transcription PCR confirmed that there was no difference in expression of CCL2, CCR2, TNF-alpha, IL-6, IL-8, and PAI1 between groups. Immunohistochemistry showed more macrophages in EAT than SAT, but there was no difference in their number or activation state between groups. In contrast to prior studies, we did not find increased inflammatory gene expression in the EAT of patients with CAD. We conclude that the specific adipose tissue depot, rather than CAD status, is responsible for the majority of differential gene expression.


Mtorc2/Akt Activation In Adipocytes Is Required For Adipose Tissue Inflammation In Tuberculosis, Nuria Martinez, Catherine Y. Cheng, Natkunam Ketheesan, Aidan Cullen, Yuefeng Tang, Josephine Lum, Kim West, Michael Poidinger, David A. Guertin, Amit Singhal, Hardy Kornfeld Jul 2019

Mtorc2/Akt Activation In Adipocytes Is Required For Adipose Tissue Inflammation In Tuberculosis, Nuria Martinez, Catherine Y. Cheng, Natkunam Ketheesan, Aidan Cullen, Yuefeng Tang, Josephine Lum, Kim West, Michael Poidinger, David A. Guertin, Amit Singhal, Hardy Kornfeld

Open Access Articles

BACKGROUND: Mycobacterium tuberculosis has co-evolved with the human host, adapting to exploit the immune system for persistence and transmission. While immunity to tuberculosis (TB) has been intensively studied in the lung and lymphoid system, little is known about the participation of adipose tissues and non-immune cells in the host-pathogen interaction during this systemic disease.

METHODS: C57BL/6J mice were aerosol infected with M. tuberculosis Erdman and presence of the bacteria and the fitness of the white and brown adipose tissues, liver and skeletal muscle were studied compared to uninfected mice.

FINDINGS: M. tuberculosis infection in mice stimulated immune cell infiltration ...


Decreasing Cb1 Receptor Signaling In Kupffer Cells Improves Insulin Sensitivity In Obese Mice, Tony Jourdan, Sarah M. Nicoloro, Zhou Zhou, Yuefei Shen, Jie Liu, Nathan J. Coffey, Resat Cinar, Grzegorz Godlewski, Bin Gao, Myriam Aouadi, Michael P. Czech, George Kunos Nov 2017

Decreasing Cb1 Receptor Signaling In Kupffer Cells Improves Insulin Sensitivity In Obese Mice, Tony Jourdan, Sarah M. Nicoloro, Zhou Zhou, Yuefei Shen, Jie Liu, Nathan J. Coffey, Resat Cinar, Grzegorz Godlewski, Bin Gao, Myriam Aouadi, Michael P. Czech, George Kunos

UMass Metabolic Network Publications

OBJECTIVE: Obesity-induced accumulation of ectopic fat in the liver is thought to contribute to the development of insulin resistance, and increased activity of hepatic CB1R has been shown to promote both processes. However, lipid accumulation in liver can be experimentally dissociated from insulin resistance under certain conditions, suggesting the involvement of additional mechanisms. Obesity is also associated with pro-inflammatory changes which, in turn, can promote insulin resistance. Kupffer cells (KCs), the liver's resident macrophages, are the major source of pro-inflammatory cytokines in the liver, such as TNF-alpha, which has been shown to inhibit insulin signaling in multiple cell types ...


Activation Of Inflammatory And Pro-Thrombotic Pathways In Acute Stress Cardiomyopathy, Timothy P. Fitzgibbons, Yvonne J. K. Edwards, Peter Shaw, Aline Iskandar, Mohamed Ahmed, Josiah T. Bote, Tejen Shah, Sumita Sinha, Robert E. Gerszten, John F. Keaney Jr., Michael R. Zile, Gerard P. Aurigemma Aug 2017

Activation Of Inflammatory And Pro-Thrombotic Pathways In Acute Stress Cardiomyopathy, Timothy P. Fitzgibbons, Yvonne J. K. Edwards, Peter Shaw, Aline Iskandar, Mohamed Ahmed, Josiah T. Bote, Tejen Shah, Sumita Sinha, Robert E. Gerszten, John F. Keaney Jr., Michael R. Zile, Gerard P. Aurigemma

Open Access Articles

Stress cardiomyopathy (SCM) is a unique cardiac disorder that more often occurs in women. SCM presents in a similar fashion as acute myocardial infarction (AMI), with chest pain, ECG changes, and congestive heart failure. The primary distinguishing feature is the absence of thrombotic coronary occlusion in SCM. How this reduction in cardiac function occurs in the absence of coronary occlusion remains unknown. Therefore, we tested the hypothesis that a targeted proteomic comparison of patients with acute SCM and AMI might identify relevant mechanistic differences. Blood was drawn in normal controls (n = 6), women with AMI (n = 12), or women with ...


Map4k4 Impairs Energy Metabolism In Endothelial Cells And Promotes Insulin Resistance In Obesity, Rachel J. Roth Flach, Marina T. Distefano, Laura V. Danai, Ozlem Senol-Cosar, Joseph C. Yawe, Mark Kelly, Lorena Garcia Menendez, Michael P. Czech Jun 2017

Map4k4 Impairs Energy Metabolism In Endothelial Cells And Promotes Insulin Resistance In Obesity, Rachel J. Roth Flach, Marina T. Distefano, Laura V. Danai, Ozlem Senol-Cosar, Joseph C. Yawe, Mark Kelly, Lorena Garcia Menendez, Michael P. Czech

UMass Metabolic Network Publications

The blood vasculature responds to insulin, influencing hemodynamic changes in the periphery, which promotes tissue nutrient and oxygen delivery and thus metabolic function. The lymphatic vasculature regulates fluid and lipid homeostasis, and impaired lymphatic function can contribute to atherosclerosis and obesity. Recent studies have suggested a role for endothelial cell (EC) Mitogen activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and lymphangiogenesis as well as atherosclerosis. Here, we show that inducible EC Map4k4 deletion in adult mice ameliorates metabolic dysfunction in obesity despite the development of chylous ascites and a concomitant striking increase in adipose tissue lymphocyte ...


Distinct Kinase-Independent Role Of Ripk3 In Cd11c+ Mononuclear Phagocytes In Cytokine-Induced Tissue Repair, Kenta Moriwaki, Sakthi Balaji, John Bertin, Peter J. Gough, Francis Ka-Ming Chan Mar 2017

Distinct Kinase-Independent Role Of Ripk3 In Cd11c+ Mononuclear Phagocytes In Cytokine-Induced Tissue Repair, Kenta Moriwaki, Sakthi Balaji, John Bertin, Peter J. Gough, Francis Ka-Ming Chan

Open Access Articles

Receptor interacting protein kinase 3 (RIPK3) induces necroptosis, a type of regulated necrosis, through its kinase domain and receptor interacting protein (RIP) homotypic interaction motif (RHIM). In addition, RIPK3 has been shown to regulate NLRP3 inflammasome and nuclear factor kappaB (NF-kappaB) activation. However, the relative contribution of these signaling pathways to RIPK3-dependent inflammation in distinct immune effectors is unknown. To investigate these questions, we generated RIPK3-GFP reporter mice. We found that colonic CD11c+CD11b+CD14+ mononuclear phagocytes (MNPs) expressed the highest level of RIPK3 in the lamina propria. Consequently, deletion of the RIPK3 RHIM in CD11c+ cells alone was sufficient ...


Hmgb1, Il-1alpha, Il-33 And S100 Proteins: Dual-Function Alarmins, Damien Bertheloot, Eicke Latz Jan 2017

Hmgb1, Il-1alpha, Il-33 And S100 Proteins: Dual-Function Alarmins, Damien Bertheloot, Eicke Latz

Open Access Articles

Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline-encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells. However, a group of proteins referred to as alarmins have both ...


The Effects Of Interleukin-10 On Skeletal Muscle Insulin Resistance And Myogenesis, Sezin Dagdeviren Dec 2016

The Effects Of Interleukin-10 On Skeletal Muscle Insulin Resistance And Myogenesis, Sezin Dagdeviren

GSBS Dissertations and Theses

Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Our lab and others have shown that a chronic low-grade inflammation takes place in skeletal muscles during diet-induced obesity, as evidenced by increased macrophage markers and pro-inflammatory cytokine levels. Interleukin (IL)-10 is a Th2-type cytokine that inhibits the synthesis and activity of pro-inflammatory cytokines and counteracts the Toll-like receptor-mediated inflammation. Our lab has previously demonstrated the preventive role of IL-10 against insulin resistance. Here, I have analyzed the effects ...


Inflammation Mediated By Jnk In Myeloid Cells Promotes The Development Of Hepatitis And Hepatocellular Carcinoma, Myoung Souk Han, Tamera Barrett, Michael A. Brehm, Roger J. Davis Apr 2016

Inflammation Mediated By Jnk In Myeloid Cells Promotes The Development Of Hepatitis And Hepatocellular Carcinoma, Myoung Souk Han, Tamera Barrett, Michael A. Brehm, Roger J. Davis

Davis Lab Publications

The cJun NH2-terminal kinase (JNK) signaling pathway is required for the development of hepatitis and hepatocellular carcinoma. A role for JNK in liver parenchymal cells has been proposed, but more recent studies have implicated non-parenchymal liver cells as the relevant site of JNK signaling. Here, we tested the hypothesis that myeloid cells mediate this function of JNK. We show that mice with myeloid cell-specific JNK deficiency exhibit reduced hepatic inflammation and suppression of both hepatitis and hepatocellular carcinoma. These data identify myeloid cells as a site of pro-inflammatory signaling by JNK that can promote liver pathology. Targeting myeloid cells with ...


A Major Role Of Insulin In Promoting Obesity-Associated Adipose Tissue Inflammation, David J. Pedersen, Adilson L Guilherme, Laura V. Danai, Lauren Heyda, Anouch Matevossian, Jessica L. Cohen, Sarah M. Nicoloro, Juerg R. Straubhaar, Hye Lim Noh, Dae Young Jung, Jason K. Kim, Michael P. Czech May 2015

A Major Role Of Insulin In Promoting Obesity-Associated Adipose Tissue Inflammation, David J. Pedersen, Adilson L Guilherme, Laura V. Danai, Lauren Heyda, Anouch Matevossian, Jessica L. Cohen, Sarah M. Nicoloro, Juerg R. Straubhaar, Hye Lim Noh, Dae Young Jung, Jason K. Kim, Michael P. Czech

Open Access Articles

OBJECTIVE: Adipose tissue (AT) inflammation is associated with systemic insulin resistance and hyperinsulinemia in obese rodents and humans. A longstanding concept is that hyperinsulinemia may promote systemic insulin resistance through downregulation of its receptor on target tissues. Here we tested the novel hypothesis that insulin also impairs systemic insulin sensitivity by specifically enhancing adipose inflammation.

METHODS: Circulating insulin levels were reduced by about 50% in diet-induced and genetically obese mice by treatments with diazoxide or streptozotocin, respectively. We then examined AT crown-like structures, macrophage markers and pro-inflammatory cytokine expression in AT. AT lipogenesis and systemic insulin sensitivity was also monitored ...


Endothelial Driven Inflammation In Metabolic Disease: A Dissertation, Anouch Matevossian Feb 2015

Endothelial Driven Inflammation In Metabolic Disease: A Dissertation, Anouch Matevossian

GSBS Dissertations and Theses

Obesity has been on the rise over the last 30 years, reaching worldwide epidemic proportions. Obesity has been linked to multiple metabolic disorders and co-morbidities such as Type 2 Diabetes Mellitus (T2DM), cardiovascular disease, non-alcoholic steatohepatitis and various cancers. Furthermore, obesity is associated with a chronic state of low-grade inflammation in adipose tissue (AT), and it is thought that insulin resistance (IR) and T2DM is associated with the inflammatory state of AT.

Endothelial cells (ECs) mediate the migration of immune cells into underlying tissues during times of inflammation, including obesity- and cardiovascular disease-associated inflammation. Cytokines and chemoattractants released from inflamed ...


Il-1 Signaling In Obesity-Induced Hepatic Lipogenesis And Steatosis, Kimberly A. Negrin, Rachel J. Roth Flach, Marina T. Distefano, Anouch Matevossian, Randall H. Friedline, Dae Young Jung, Jason K. Kim, Michael P. Czech Sep 2014

Il-1 Signaling In Obesity-Induced Hepatic Lipogenesis And Steatosis, Kimberly A. Negrin, Rachel J. Roth Flach, Marina T. Distefano, Anouch Matevossian, Randall H. Friedline, Dae Young Jung, Jason K. Kim, Michael P. Czech

Open Access Articles

Non-alcoholic fatty liver disease is prevalent in human obesity and type 2 diabetes, and is characterized by increases in both hepatic triglyceride accumulation (denoted as steatosis) and expression of pro-inflammatory cytokines such as IL-1beta. We report here that the development of hepatic steatosis requires IL-1 signaling, which upregulates Fatty acid synthase to promote hepatic lipogenesis. Using clodronate liposomes to selectively deplete liver Kupffer cells in ob/ob mice, we observed remarkable amelioration of obesity-induced hepatic steatosis and reductions in liver weight, triglyceride content and lipogenic enzyme expressions. Similar results were obtained with diet-induced obese mice, although visceral adipose tissue macrophage ...


Tlr Sorting By Rab11 Endosomes Maintains Intestinal Epithelial-Microbial Homeostasis, Shiyan Yu, Yingchao Nie, Y. Tony Ip, Nan Gao Sep 2014

Tlr Sorting By Rab11 Endosomes Maintains Intestinal Epithelial-Microbial Homeostasis, Shiyan Yu, Yingchao Nie, Y. Tony Ip, Nan Gao

UMass Center for Clinical and Translational Science Supported Publications

Compartmentalization of Toll-like receptors (TLRs) in intestinal epithelial cells (IECs) regulates distinct immune responses to microbes; however, the specific cellular machinery that controls this mechanism has not been fully identified. Here we provide genetic evidences that the recycling endosomal compartment in enterocytes maintains a homeostatic TLR9 intracellular distribution, supporting mucosal tolerance to normal microbiota. Genetic ablation of a recycling endosome resident small GTPase, Rab11a, a gene adjacent to a Crohn's disease risk locus, in mouse IECs and in Drosophila midgut caused epithelial cell-intrinsic cytokine production, inflammatory bowel phenotype, and early mortality. Unlike wild-type controls, germ-free Rab11a-deficient mouse intestines failed ...


Evaluation Of The Contribution Of Multiple Damps And Damp Receptors In Cell Death-Induced Sterile Inflammatory Responses, Hiroshi Kataoka, Hajime Kono, Zubin Patel, Kenneth L. Rock Aug 2014

Evaluation Of The Contribution Of Multiple Damps And Damp Receptors In Cell Death-Induced Sterile Inflammatory Responses, Hiroshi Kataoka, Hajime Kono, Zubin Patel, Kenneth L. Rock

Open Access Articles

When cells die by necrosis in vivo they stimulate an inflammatory response. It is thought that this response is triggered when the injured cells expose proinflammatory molecules, collectively referred to as damage associated molecular patterns (DAMPs), which are recognized by cells or soluble molecules of the innate or adaptive immune system. Several putative DAMPs and/or their receptors have been identified, but whether and how much they participate in responses in vivo is incompletely understood, and they have not previously been compared side-by-side in the same models. This study focuses on evaluating the contribution of multiple mechanisms that have been ...


Complex Roles Of Macrophages In Lipid Metabolism And Metabolic Disease: A Dissertation, Kimberly A. Negrin Apr 2014

Complex Roles Of Macrophages In Lipid Metabolism And Metabolic Disease: A Dissertation, Kimberly A. Negrin

GSBS Dissertations and Theses

The worldwide prevalence of obesity and metabolic disease is increasing at an exponential rate and current projections provide no indication of relief. This growing burden of obesity-related metabolic disorders, including type 2 diabetes mellitus (T2DM), highlights the importance of identifying how lifestyle choices, genetics and physiology play a role in metabolic disease and place obese individuals at a greater risk for obesity-related complications including insulin resistance (IR). This increased risk of IR, which is characterized by a decreased response to insulin in peripheral tissues including adipose tissue (AT) and liver, is associated with a chronic, low grade inflammatory state; however ...


Rip3: A Molecular Switch For Necrosis And Inflammation, Kenta Moriwaki, Francis Ka-Ming Chan Aug 2013

Rip3: A Molecular Switch For Necrosis And Inflammation, Kenta Moriwaki, Francis Ka-Ming Chan

University of Massachusetts Medical School Faculty Publications

The receptor-interacting protein kinase 3 (RIP3/RIPK3) has emerged as a critical regulator of programmed necrosis/necroptosis, an inflammatory form of cell death with important functions in pathogen-induced and sterile inflammation. RIP3 activation is tightly regulated by phosphorylation, ubiquitination, and caspase-mediated cleavage. These post-translational modifications coordinately regulate the assembly of a macromolecular signaling complex termed the necrosome. Recently, several reports indicate that RIP3 can promote inflammation independent of its pronecrotic activity. Here, we review our current understanding of the mechanisms that drive RIP3-dependent necrosis and its role in different inflammatory diseases.


Local Macrophage Proliferation In Adipose Tissue Is A Characteristic Of Obesity-Associated Inflammation: A Dissertation, Shinya U. Amano Mar 2013

Local Macrophage Proliferation In Adipose Tissue Is A Characteristic Of Obesity-Associated Inflammation: A Dissertation, Shinya U. Amano

GSBS Dissertations and Theses

Obesity and diabetes are major public health problems facing the world today. Extending our understanding of adipose tissue biology, and how it changes in obesity, will hopefully better equip our society in dealing with the obesity epidemic. Macrophages and other immune cells accumulate in the adipose tissue in obesity and secrete cytokines that can promote insulin resistance. Adipose tissue macrophages (ATMs) are thought to originate from bone marrow-derived monocytes, which infiltrate the tissue from the circulation. Much work has been done to demonstrate that inhibition of monocyte recruitment to the adipose tissue can ameliorate insulin resistance. While monocytes can enter ...


Role Of Inflammation In Diet-Induced Obesity: A Dissertation, Sophia Kogan Mar 2013

Role Of Inflammation In Diet-Induced Obesity: A Dissertation, Sophia Kogan

GSBS Dissertations and Theses

Obesity results from expansion of white adipose tissue. The inability of white adipose tissue to adequately store lipids leads to ectopic deposition of lipids in non-adipose tissue that can lead to systemic insulin resistance. It is well known that insulin resistance correlates with inflammation of adipose tissue in obese animals and humans. Decreasing inflammation in the adipose tissue has been proven as a therapeutic strategy for improvement of insulin sensitivity in vivo. Numerous factors secreted by immune cells, including macrophages, have been suggested as regulating adipose tissue insulin sensitivity.

In the first part of my thesis, I describe the role ...