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Principal Investigator: Yun Sok Lee
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $379,200
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY/ABSTRACT
The prevalence of Type 2 diabetes mellitus (T2DM) is rising dramatically on a global basis and has now
reached epidemic proportions. Current anti-diabetic therapeutics are available, but are inadequate to fully
control T2DM in most patients, resulting in a great deal of morbidity and mortality. Insulin resistance is a
major etiologic cause underlying T2DM. However, there are no clinical options to directly improve insulin
sensitivity, except for thiazolidinediones, which are infrequently used due to unwanted side effects.
Obesity is the most common cause of insulin resistance, and accumulating evidence indicates that
obesity-induced inflammation (or metaflammation) is an important cause of insulin resistance and obesity-
associated metabolic complications. Therefore, there are huge unmet medical needs for the prevention
and treatment of metaflammation. However, it is not known how chronic metaflammation is initiated and
propagates during the development of obesity, and why it is not resolved. Macrophages are the major
immune cell type mediating metaflammation, and evidence suggest that changes in macrophage
mitochondria activity can promote pro-inflammatory activation and M1-like polarization of macrophages.
However, how mitochondrial activity is regulated during the course of M1- or M2-like macrophage
polarization, especially in the obese/energy-excess adipose tissue microenvironment is not clearly
understood. We will tackle the question of obesity-induced metaflammation from a new angle, focusing on
mitochondrial biology with a novel target and hypothesis. Our preliminary suggest that ANT2 is a
mitochondrial sensor of FFAs in macrophages to induces mitochondria remodeling favoring pro-
inflammatory activation. Since the major source of increased plasma FFAs in obesity is adipocytes, FFA-
induced ANT2 activation can provide an adipose tissue-specific pro-inflammatory macrophage activation
mechanism in obesity. Interestingly, the effect of macrophage ANT2 KO includes the changes in
mitochondrial number, mass, and capacity, whereas adipocyte or myocyte ANT2 KO does not cause
these changes. This suggest that macrophage ANT2 mediates mitochondria remodeling through a cell
type-specific mechanism that is distinct from ANT2 effects in adipocytes and myocytes. We will explore
whether macrophage ANT2 mediates the initiation and/or maintenance of metaflammation in obese
adipose tissue. We will then assess how ANT2 regulates mitochondrial capacity, dynamics, and
metabolism to support the pro-inflammatory activation of macrophages, and how macrophage ANT2
activation induces insulin resistance. If successful, our studies will provide a novel mechanism for how
obesity induces tissue-selective metaflammation and insulin resistance. Successful completion of the
proposed study will identify ANT2 as a potential target for novel therapeutics to prevent metaflammation,
insulin resistance, and glucose intolerance.
Terms: <2,4-thiazolidinedione><ADP Translocase><ADP,ATP Carrier><ADP,ATP Translocator Protein><ATP Translocase><ATP-ADP Translocase><Active Oxygen><Adenine Nucleotide Translocase><Adipocytes><Adipose Cell><Adipose tissue><Adult-Onset Diabetes Mellitus><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-diabetic Agents><Anti-diabetic Drugs><Anti-inflammatory><Automobile Driving><Biology><Blood Plasma><Blood monocyte><Body Tissues><Causality><Cell Communication and Signaling><Cell Signaling><Chronic><Clinical><Cues><Data><Diabetes Mellitus><Dysfunction><Electron Transport><Epidemic><Etiology><Exhibits><Fat Cells><Fatty Liver><Fatty Tissue><Free Fatty Acids><Functional disorder><Gene Expression><Generalized Growth><Glitazones><Glucose Intolerance><Glucose Metabolic Disorders><Glucose Metabolism Disorders><Growth><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Immune><Immunes><Inflammation><Inflammatory><Inner mitochondrial membrane><Insulin Resistance><Intermediary Metabolism><Intracellular Communication and Signaling><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Lipocytes><Liver Cells><Liver Steatosis><Macrophage><Macrophage Activation><Maintenance><Marrow monocyte><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Medical><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Metabolic><Metabolic Processes><Metabolism><Micro RNA><MicroRNAs><Mitochondria><Mitochondrial Proteins><Molecular><Morbidity><Morbidity - disease rate><Muscle Cells><Myelogenous><Myeloid><Myocytes><Mφ><NASH><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Nonesterified Fatty Acids><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Null Mouse><Nutritional><Obese Mice><Obesity><Oxygen Radicals><Patients><Phagocytosis><Phenotype><Physiopathology><Plasma><Plasma Serum><Play><Prevalence><Prevention><Pro-Oxidants><Process><Production><Reactive Oxygen Species><Regulation><Reporting><Respiration><Reticuloendothelial System, Serum, Plasma><Role><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Source><Stable Diabetes Mellitus><Surface Proteins><System><T2 DM><T2D><T2DM><Testing><Therapeutic><Thiazolidinediones><Tissue Growth><Tissues><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><adipose><adiposity><adult onset diabetes><anti-diabetic><biological signal transduction><causation><cell type><corpulence><diabetes><disease causation><driving><electron transfer><exosome><extracellular><flexibility><flexible><hepatic steatosis><hepatosteatosis><improved><insulin resistant><insulin sensitivity><insulin signaling><insulin tolerance><ketosis resistant diabetes><maturity onset diabetes><miRNA><miRNAs><mitochondrial><mitochondrial dysfunction><monocyte><mortality><mouse development><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><non-alcohol induced steatohepatitis><non-alcoholic steato-hepatitis><non-alcoholic steatohepatitis><nonalcoholic steato-hepatitis><nonalcoholic steatohepatitis><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><nutritious><ob/ob mouse><obesity development><ontogeny><pathophysiology><prevent><preventing><respiratory mechanism><response><sensor><side effect><social role><thiazolidinedione><trafficking><type 2 DM><type II DM><type two diabetes><white adipose tissue><yellow adipose tissue>