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Principal Investigator: Dan Winer
Organization: BUCK INSTITUTE FOR RESEARCH ON AGING
Fiscal Year: 2024
Award: $543,472
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY / ABSTRACT
Obesity is a major global health concern. When people become obese, the body fails to respond well to insulin,
called insulin resistance. This process can lead to high blood sugar triggering type 2 diabetes, though the
underlying causes are poorly understood. We have shown that inflammation in the liver and fat are major
causes of insulin resistance. Fat tissue in mice and people have increased immune cells, T and B cells, that
cause inflammation. This net inflammation is one key link leading to obesity related insulin resistance.
The current research proposal investigates how the B cell behaves during early and later stages of obesity.
Interestingly, here we describe insulin itself as a major factor dictating the behavior of B cells in obesity.
Specifically, we show that insulin binding to its receptor on B cells causes the B cells to proliferate, make
inflammatory proteins and antibodies. This process contributes to establishment of insulin resistance since
when mice are genetically engineered to contain B cells lacking insulin receptors, the mice show improved
blood sugar levels when fed a diabetes inducing high fat diet for a limited time. However, this same pathway
may also limit immune cell function during longstanding obesity. Indeed, we see insulin resistance inside
immune cells with longer duration high fat diet, and compromised response to viral lung infection in mice with
insulin resistant immune systems. Thus, we believe that insulin is one critical factor which primes the immune
system to respond to danger signals in the environment and fuel its function. During establishment of obesity
and insulin resistance, insulin boost activation and metabolism of immune cells to heighten inflammation when
responding to danger signals; however, as the pathway becomes resistant, these immune cells with high basal
inflammatory tone are crippled to respond to new challenge such as virus. This mechanism also likely explains
in part why the obese cannot fight off viruses like influenza or SARS-2 coronaviruses.
In this proposal we will use genetically engineered mouse models to map out how insulin controls B cell
immunology during different durations of obesogenic diet. First, we will look at insulin’s capacity to control B
cell inflammation, metabolic programming and antibody production. Next, we will understand how diet induced
obesity communicates via insulin action on B cells to control blood sugar. This aim includes mapping out
insulin receptor docking sites on immunological target genes. Then we will characterize the immunological
consequences of immune cell insulin resistance during lung virus infection in a mouse model of influenza.
Finally, we will determine the relative mechanistic roles for obesity related danger pattern signaling in
contributing to the insulin resistant B cell inflammatory state. These experiments will give crucial new insights
into immune cell influence on obesity, and how obesity potentially cripples immunity, which has relevance to
many conditions, including lethal viruses such as our current pandemic.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><7S Gamma Globulin><Ab response><Activities of Daily Living><Activities of everyday life><Acute><Adipose tissue><Adjuvant><Adult-Onset Diabetes Mellitus><Aging><Antibodies><Antibody Formation><Antibody Production><Automobile Driving><Autoregulation><B blood cells><B cell><B cells><B-Cell Activation><B-Cells><B-Lymphocytes><B-cell><Behavior><Beta Cell><Binding><Blood Glucose><Blood Sugar><Body Tissues><Brain><Brain Nervous System><COVID-19><COVID-19 related risk><COVID-19 risk><COVID-19 risk factor><COVID-19 virus><COVID19 virus><CV-19><Cell Body><Cell Communication and Signaling><Cell Function><Cell Nucleus><Cell Physiology><Cell Process><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Function><Cellular Metabolic Process><Cellular Physiology><Cellular Process><Cellular biology><Chronic><CoV-2><CoV2><Communication><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><D-Glucose><Development><Dextrose><Diabetes Mellitus><Diet><Disease><Disorder><Docking><Dysfunction><Encephalon><Environment><Fats><Fatty Tissue><Fatty acid glycerol esters><Frequencies><Functional disorder><GEM model><GEMM model><Gene Transcription><Genes><Genetic Transcription><Genetically Engineered Mouse><Glucose><Grippe><Health><High Fat Diet><Homeostasis><Human><Humulin R><Hyperinsulinemia><Hyperinsulinism><IgG><Immune><Immune Targeting><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunoglobulin G><Immunologic><Immunological><Immunologically><Immunologics><Immunology><Immunomodulation><Infection><Inflammation><Inflammatory><Inflammatory Response><Influenza><Insulin><Insulin Cell><Insulin Receptor><Insulin Receptor Protein-Tyrosine Kinase><Insulin Resistance><Insulin Secreting Cell><Insulin Signaling Pathway><Insulin-Dependent Tyrosine Protein Kinase><Intermediary Metabolism><Intracellular Communication and Signaling><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out Mice><Knockout Mice><Knowledge><Length of Life><Link><Lipids><Liver><Longevity><Lung><Lung Respiratory System><Lung infections><Maps><Maturity-Onset Diabetes Mellitus><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modern Man><Molecular Interaction><Murine><Mus><Muscle><Muscle Tissue><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Nuclear Translocation><Nucleus><Null Mouse><Obese Mice><Obesity><Organism><Pathogenicity><Pathway interactions><Pattern><Persons><Physiological Homeostasis><Physiopathology><Play><Process><Production><Proliferating><Proteins><RNA Expression><Receptor Protein><Receptor Signaling><Regular Insulin><Reporting><Research Proposals><Resistance><Risk Factors><Role><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CO-V2><SARS-COVID-2><SARS-CoV disease><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Subcellular Process><T-Cells><T-Lymphocyte><T2 DM><T2D><T2DM><TLR protein><Time><Tissues><Toll-Like Receptor Family Gene><Toll-like receptors><Transcription><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Viral><Viral Diseases><Virus><Virus Diseases><Visceral><Work><Wuhan coronavirus><activated B cells><adipose><adiposity><adult onset diabetes><antibody biosynthesis><biological signal transduction><cell biology><cell metabolism><cellular metabaolism><corona virus><coronavirus disease 2019><coronavirus disease 2019 risk><coronavirus disease 2019 risk factor><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><corpulence><current pandemic><cytokine><daily living function><daily living functionality><death risk><developmental><diabetes><diet-associated obesity><diet-induced obesity><diet-related obesity><diets><driving><experiment><experimental research><experimental study><experiments><fighting><flu infection><flu virus infection><functional ability><functional capacity><genetically engineered mouse model><genetically engineered murine model><global health><hCoV19><hepatic body system><hepatic organ system><high risk><immune modulation><immune regulation><immunoglobulin biosynthesis><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><improved><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><insight><insulin resistant><insulin signaling><insulin tolerance><ketosis resistant diabetes><living system><maturity onset diabetes><mortality risk><mouse model><murine model><muscular><nCoV2><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ob/ob mouse><obesigenic><obesogenic><pathophysiology><pathway><present pandemic><pulmonary><pulmonary infections><receptor><resistant><response><risk associated with COVID-19><risk factor associated with COVID-19><risk factor related to COVID-19><risk related to COVID-19><social role><thymus derived lymphocyte><type 2 DM><type II DM><type two diabetes><viral infection><virus infection><virus-induced disease><white adipose tissue><yellow adipose tissue><β-cell><β-cells><βCell>