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Principal Investigator: Ling Zhao
Organization: UNIVERSITY OF TENNESSEE KNOXVILLE
Fiscal Year: 2022
Award: $445,534
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary/Abstract
Obesity remains one of the biggest public health challenges worldwide. Obesity is associated with various
comorbidities, including type 2 diabetes, dyslipidemia, and cardiovascular diseases, leading to a shorter lifespan
and higher medical costs. Recent studies have indicated that obesity is also associated with the high prevalence
and severity of COVID-19, an infectious disease caused by coronavirus SARS-CoV-2. Therefore, novel
approaches and new generations of researchers are still needed to treat and prevent human obesity. Brown
adipose tissue (BAT), a fat type responsible for non-shivering thermogenesis and now known to exist in adult
humans, has emerged as a novel target to increase energy expenditure and improve systemic metabolism for
obesity prevention. In addition, a browning process, i.e., the appearance of beige adipocytes within white adipose
tissue (WAT) depots in response to cold or other stimulations, has also been reported. However, to our
knowledge, there are still no practical and effective ways to stimulate thermogenesis in humans except for cold
exposure or β-adrenergic stimulation, which is associated with side effects and low compliance. We have
discovered that 17,18-epoxyeicosatetraenoic acid (EEQ, an n-3 polyunsaturated fatty acid eicosapentaenoic
acid (EPA)-derived epoxy fatty acid) at a much low dose, when stabilized by a pharmacological inhibitor of
soluble epoxide hydrolase (the enzyme that degrades epoxy fatty acids), significantly increased core body
temperature and heat production and improved blood triglycerides and glucose levels in diet-induced obesity.
The thermogenic efficacy of 17,18-EEQ is better than 19,20-epoxydocosapentaenoic acid (EDP, a
docosahexaenoic acid (DHA)-derived epoxy fatty acid) and much potent than the reported EPA or fish oil
enriched with EPA and DHA. Therefore, the goal of this proposal is to (Aim 1) elucidate the molecular and
biochemical mechanisms by which 17,18-EEQ promotes thermogenesis in mouse brown and beige adipocytes
in vitro compared with 19,20-EDP and (Aim 2) determine the efficacy of 17,18-EEQ compared with 19,20-EDP
in increasing thermogenesis in human brown and beige adipocytes and increasing energy expenditure and
improving metabolism in transplanted mice in vivo. In light of the critical roles of thermogenesis in human obesity
treatment and prevention, it is urgent to identify novel, effective, and safe agents and molecular targets to
promote thermogenesis and increase energy expenditure. The outcomes for this proposed project are (1)
significant advancement of the understanding of 17,18-EEQ biology, leading to novel strategies to boost
thermogenesis in brown and beige adipocytes; (2) extensive exposure and training of both undergraduate and
graduate students to biomedical research in the areas of adipocyte biology and obesity.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><Acids><Adipocytes><Adipose Cell><Adipose tissue><Adrenergic Agents><Adrenergic Drugs><Adrenergics><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Affect><Animal Model><Animal Models and Related Studies><Animals><Appearance><Arachidonic Acid Cyclooxygenase><Area><BAT uncoupling protein><Biochemical><Biology><Biomedical Research><Blood><Blood Reticuloendothelial System><Blood Vessels><Body Temperature><Body Weight><Brown Adipose Tissue><Brown Fat><COVID disease severity><COVID severity><COVID-19 disease severity><COVID-19 severity><COVID-19 virus><COVID19 disease severity><COVID19 severity><COVID19 virus><Cardiovascular Diseases><Cell Body><Cell Line><Cell Transplantation><CellLine><Cells><Cellular Expansion><Cellular Growth><CoV-2><CoV2><Communicable Diseases><Coronaviridae><Coronavirus><Cyclo-Oxygenase><Cyclooxygenase><Cytochrome P-450><Cytochrome P-450 Enzyme System><Cytochrome P450><Cytochrome P450 Family Gene><D-Glucose><Dextrose><Diet><Differentiation and Growth><Docosahexaenoate><Docosahexaenoic Acids><Docosahexenoic Acids><Dose><Dyslipidemias><Eicosapentaenoic Acid><Energy Expenditure><Energy Metabolism><Engineering><Enzyme Gene><Enzymes><Epoxide Hydrases><Epoxide Hydratases><Epoxide hydrolase><Epoxides><Epoxy Compounds><Fat Cells><Fats><Fatty Acid Cyclo-Oxygenase><Fatty Acid Metabolism Pathway><Fatty Acids><Fatty Tissue><Fatty acid glycerol esters><Fish Oils><Generations><Genes><Glucose><Glycols><Goals><Heat Production><Hibernating Gland><High Fat Diet><High Prevalence><Human><Hydroperoxide Cyclase><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><In Vitro><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Intermediary Metabolism><Investigators><Ketosis-Resistant Diabetes Mellitus><Length of Life><Light><Linoleate-Oxygen Oxidoreductase><Lipocytes><Lipolysis><Lipoxidase><Lipoxygenase><Longevity><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Mediating><Medical Care Costs><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modern Man><Molecular><Molecular Target><Murine><Mus><N-3 polyunsaturated fatty acid><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Obesity><Outcome><P450><PGH Synthase><PGH2 Synthetase><Pain><Painful><Pharmacology><Photoradiation><Play><Polyunsaturated Fatty Acids><Process><Prostaglandin Cyclo-Oxygenase><Prostaglandin Cyclooxygenase><Prostaglandin Endoperoxide Synthetase><Prostaglandin G-H Synthase><Prostaglandin H Synthase><Prostaglandin H2 Synthetase><Prostaglandin Synthase><Prostaglandin Synthetase><Prostaglandin-Endoperoxide Synthase><Proteins><Public Health><RNA Seq><RNA sequencing><RNAseq><Reporting><Research Personnel><Researchers><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 disease severity><SARS-CoV-2 severity><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Seafood Oil><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 CoV 2><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Signaling Molecule><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Strains Cell Lines><Stromal Cells><Supplementation><T2 DM><T2D><T2DM><Technology><Thermogenesis><Timnodonic Acid><Training><Transplantation><Triacylglycerol><Triglycerides><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Wuhan coronavirus><adipocyte biology><adipose><adiposity><adult onset diabetes><adulthood><brown adipose tissue uncoupling protein><cardiovascular disorder><carotene oxidase><cell growth><cell type><co-morbid><co-morbidity><comorbidity><corona virus><coronavirus disease 2019 disease severity><coronavirus disease 2019 severity><coronavirus disease 2019 virus><coronavirus disease severity><coronavirus disease-19 virus><corpulence><cultured cell line><diet-associated obesity><diet-induced obesity><diet-related obesity><diets><diol><fat metabolism><fatty acid metabolism><feeding><graduate student><hCoV19><human subject><immunosuppressed patient><improved><in vivo><inhibitor><insight><ketosis resistant diabetes><life span><lifespan><lipid metabolism><maturity onset diabetes><medical costs><model of animal><model organism><n-3 PUFA><n-3-PUFA><nCoV2><new approaches><novel><novel approaches><novel strategies><novel strategy><obesity intervention><obesity prevention><obesity therapy><obesity treatment><oxidation><prevent><prevent obesity><preventing><protein expression><response><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 severity><side effect><social role><subcutaneous><subdermal><thermogenin><transcriptome sequencing><translational study><transplant><type 2 DM><type II DM><type two diabetes><uncoupling protein 1><undergrad><undergraduate><undergraduate student><uptake><vascular><white adipose tissue><yellow adipose tissue>