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Principal Investigator: Lev Becker
Organization: UNIVERSITY OF CHICAGO
Fiscal Year: 2024
Award: $490,784
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
ABSTRACT
Visceral obesity associates with insulin resistance and chronic inflammation, which are major risk factors for
the metabolic syndrome, diabetes, and cardiovascular disease. Although the cellular hallmark of obesity is
neutral lipid expansion in adipocytes, adipose tissue of obese mice and humans also accumulate
macrophages and other leukocytes. It is well accepted that adipose tissue macrophages (ATMs) play a critical
role in systemic insulin resistance, suggesting that inflammatory mediators produced by ATMs are important
factors linking excess fat mass to insulin sensitivity, glucose intolerance, and increased atherosclerotic risk.
Understanding the mechanistic basis of the pro-inflammatory ATM phenotype and ATM function is required to
devise new strategies for attenuating inflammation in metabolic disease.
Pro-inflammatory pathways in ATMs are commonly attributed to classical activation (exposure to bacteria, M1),
establishing molecular links between innate immunity and metabolic dysfunction. Recent studies, including
work from our lab, suggest that M1 activation fails to accurately represent the complex phenotype of ATMs in
vivo. We have shown that ATMs in obese adipose tissue from humans and mice adopt a unique ‘metabolically
activated’ (MMe) phenotype that is distinct from the M1 phenotype. Inhibiting MMe activation of macrophages
in vivo, attenuates ATM inflammation and improved glucose tolerance in mice. Moreover, the abundance of
MMe-like ATMs in visceral fat is positively correlated with insulin resistance in patients controlled for adiposity.
These findings underscore the pathophysiological importance of MMe macrophages in mice and humans.
Although MMe and M1 macrophages are both characterized by increased expression of NFkB-induced
inflammatory cytokines (ie. Tnfa, Il1b, Il6), our preliminary studies demonstrate that the upstream signaling
cascades driving NFkB activation are remarkably distinct. We provide evidence for a novel fatty acid-driven,
ROS-dependent, tyrosine-kinase mediated, pro-inflammatory signaling cascade in MMe macrophages.
Targeting this ‘metabolically activated NFkB’ (Me-NFkB) pathway at any point selectively attenuates
inflammatory cytokine expression by MMe macrophages.
Our work has positioned us to test the innovative hypothesis that this Me-NFkB pathway promotes ATM
inflammation and insulin resistance during obesity but is dispensable for inflammation required for
host defense during infection. Specifically, we plan to 1) Delineate the Me-NFkB pathway that drives
inflammation in MMe macrophages, and 2) Determine if targeting the Me-NFkB pathway improves insulin
sensitivity in mice. Overall, our proposed studies aim to demonstrate that macrophage inflammation in
metabolic disease can be attenuated without blocking these same cytokines in bacterial infection, a conceptual
milestone that may lead to an improved anti-inflammatory strategy in the clinic.
Terms: <Abdominal obesity><Adipocytes><Adipose Cell><Adipose tissue><Adopted><Adult-Onset Diabetes Mellitus><Agammaglobulinaemia tyrosine kinase><Android fat distribution><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Attenuated><Automobile Driving><B cell progenitor kinase><Bacteria><Bacterial Infections><Blood leukocyte><Bruton's tyrosine kinase><Cardiovascular Diseases><Cell Communication and Signaling><Cell Signaling><Cell surface><Central obesity><Centripetal obesity><Chronic><Clinic><Clinical><Complex><DNA Therapy><Data><Diabetes Mellitus><Disease><Disorder><Drug Targeting><Drug Therapy><EPH- and ELK-Related Tyrosine Kinase><EPH-and ELK-Related Kinase><Ephrin Type-A Receptor 8><Ephrin Type-A Receptor 8 Precursor><Event><Experimental Animal Model><Exposure to><Fat Cells><Fats><Fatty Acids><Fatty Liver><Fatty Tissue><Fatty acid glycerol esters><Funding><Gene Transfer Clinical><Genetic><Genetic Intervention><Glucose Intolerance><Goals><Host Defense><Human><Immunoglobulin Enhancer-Binding Protein><Infection><Inflammation><Inflammation Mediators><Inflammatory><Innate Immunity><Insulin Resistance><Intracellular Communication and Signaling><KO mice><Ketosis-Resistant Diabetes Mellitus><Kinases><Knock-out Mice><Knockout Mice><Leukocytes><Leukocytes Reticuloendothelial System><Link><Lipids><Lipocytes><Liver Steatosis><Macrophage><Macrophage Activation><Marrow leukocyte><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic dysfunction><Metabolic syndrome><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Myeloid Cells><Mφ><NF-kB><NF-kappa B><NF-kappaB><NFKB><NIDDM><Native Immunity><Natural Immunity><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Non-Specific Immunity><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nonspecific Immunity><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Null Mouse><Obese Mice><Obesity><PTK Inhibitors><Pathway interactions><Patients><Peptide Signal Sequences><Peritonitis><Pharmacotherapy><Phenotype><Phosphotransferase Gene><Phosphotransferases><Play><Position><Positioning Attribute><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Protein Modification><Protein Tyrosine Kinase><Protein Tyrosine Kinase EEK><Protein Tyrosine Kinase Inhibitors><Publishing><Reporting><Risk Factors><Role><SYK><SYK gene><Signal Pathway><Signal Peptide><Signal Sequences><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Source><Spleen><Spleen Reticuloendothelial System><Spleen Tyrosine Kinase><Stable Diabetes Mellitus><Stimulus><T2 DM><T2D><T2DM><TK Inhibitors><Testing><Therapeutic><Therapeutic Intervention><Thesaurismosis><Transcription Factor NF-kB><Transphosphorylases><Treatment Efficacy><Truncal obesity><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Tyrosine Kinase><Tyrosine Kinase Inhibitor><Tyrosine-Protein Kinase Receptor EEK><Tyrosine-Protein Kinase SYK><Tyrosine-Specific Protein Kinase><Tyrosylprotein Kinase><Visceral fat><White Blood Cells><White Cell><Work><adipose><adiposity><adult onset diabetes><atherosclerosis risk><atherosclerotic risk><attenuate><attenuates><bacteria infection><bacterial disease><biological signal transduction><bpk protein><btk protein><cardiovascular disorder><corpulence><cytokine><diabetes><driving><drug action><drug treatment><fighting><gene repair therapy><gene therapy><gene-based therapy><genetic approach><genetic strategy><genetic therapy><genomic therapy><glucose tolerance><hepatic steatosis><hepatosteatosis><human tissue><hydroxyaryl protein kinase><improved><in vivo><inflammatory mediator><innovate><innovation><innovative><insulin resistant><insulin sensitivity><insulin signaling><insulin tolerance><intervention efficacy><intervention therapy><kappa B Enhancer Binding Protein><ketosis resistant diabetes><maturity onset diabetes><metabolism disorder><mouse model><murine model><new approaches><novel><novel approaches><novel strategies><novel strategy><nuclear factor kappa beta><ob/ob mouse><obese patients><pathway><patients with obesity><protein signal sequence><social role><therapeutic efficacy><therapy efficacy><type 2 DM><type II DM><type two diabetes><tyrosyl protein kinase><visceral obesity><white adipose tissue><white blood cell><white blood corpuscle><yellow adipose tissue>