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Principal Investigator: John Michael Stafford
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $83,238
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Obesity impairs glucose and lipid metabolism and increases the risk of coronary heart disease (CHD). Women
with obesity have ~1/2 the risk of CHD as obese men. The risk of CHD goes up with menopause, but by
mechanisms distinct from obese men. The protection conferred by estrogen signaling in females is lost with
diabetes due to undefined mechanisms. The liver plays an important part in estrogen-regulated metabolism. Our
goal is to therapeutically target the beneficial hepatic actions of estrogens in males and females and discover
the mechanisms by which diabetes interacts with liver estrogen signaling to put females at high CHD risk.
In the last funding cycle of this project, we used mouse models and metabolic tracers to discover that estrogen
signaling through hepatic estrogen receptor alpha (ERa) protects against several key aspects of obesity-
associated metabolic disease. We showed that, 1) whole body and liver insulin sensitivity are improved; 2) fatty
liver is diminished by increasing fatty acid oxidation and increasing liver VLDL output; 3) atherosclerosis is
reduced by improving HDL’s cholesterol efflux and anti-inflammatory properties, and by increasing liver
cholesterol delivery (reverse cholesterol transport). While examining the pathways by which hepatic ERa confers
protection for females, we made the surprising observation that it has protective effects in obese males also.
Hepatic ERa in males, 1) decreases liver fat; 2) improves liver and whole-body insulin sensitivity; 3) improves
HDL cholesterol efflux capacity. The goal of AIM1 is to amplify the beneficial effects of the hepatic ERa in male
and female mice by defining approaches to therapeutically target estrogen signaling in the liver.
Diabetic women have the same elevated CHD risk as diabetic men. We found that hyperglycemia induces
hepatic stress, negating the benefit of hepatic estrogen signaling. Whether hyperglycemia or some aspect of
glycemic control is the mechanism by which diabetes negates the protective effect of being female remains to
be determined. We will explore mechanisms for this important biology in AIM2. Our overarching hypothesis is
that targeted hepatic estrogen signaling will benefit glucose metabolism, fatty liver, HDL function, and
atherosclerosis in obese males and females. In contrast, hyperglycemia leads to accumulation of liver glucose
metabolites that activate Carbohydrate Response Element Binding Protein and counters the benefits of ERa.
Our hypothesis is innovative because we propose that targeting ERa in hepatocytes will limit many aspects
of obesity-associated disease in both females and males without unfavorable estrogen actions on other tissues.
We will also define a critical mechanism for the sex-specific impact of diabetes on CHD risk factors in females.
Our techniques are innovative because we are applying isotopic tracers and tissue-targeted, sex-based,
therapeutics to distinguish estradiol action and glucose metabolism at the liver from profound whole-body effects.
Our studies are significant because we will use knowledge of sex differences physiology to develop targeted
treatments that benefit both sexes. We will define a pathway that links diabetes to severe outcomes in women.
Terms: <Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antidiabetic Hormone><Aquadiol><Area><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Attenuated><Binding Proteins><Biology><Body Tissues><Carbohydrates><Cardiovascular Diseases><Cell Communication and Signaling><Cell Signaling><Cholesterol><Chronic><Clampings><Clinical Trials><Closure by clamp><Coronary Disease><Coronary heart disease><Corynebacterium Diphtheriae Toxin><D-Glucose><Dependence><Dextrose><Diabetes Mellitus><Differences between sexes><Differs between sexes><Dimenformon><Diogyn><Diogynets><Diphtheria Toxin><Disease><Disorder><ERalpha><ERα><ESR1><ESR1 gene><Estrace><Estradiol><Estradiol Receptor alpha><Estradiol Receptor α><Estradiol-17 beta><Estradiol-17beta><Estraldine><Estrogen Receptor 1><Estrogen Receptor alpha><Estrogen Receptor α><Estrogenic Agents><Estrogenic Compounds><Estrogens><Fats><Fatty Liver><Fatty acid glycerol esters><Female><Funding><Glucagon><Glucose><Glukagon><Glycogen><Goals><HDL><HDL Cholesterol><HDL Cholesterol Lipoproteins><HDL Lipoproteins><HG-Factor><Heavy Lipoproteins><Hepatic><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><High Density Lipoprotein Cholesterol><High Density Lipoproteins><High density lipoprotein><Human><Hyperglycemia><Hyperglycemic-Glycogenolytic Factor><Hyperinsulinemia><Hyperinsulinism><Impairment><Intermediary Metabolism><Intracellular Communication and Signaling><Isotopes><Knock-out><Knockout><Knowledge><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Lipids><Liver><Liver Cells><Liver Steatosis><Long-Term Effects><Longterm Effects><Mediating><Menopause><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><NIDDK><NIH><NR3A1><National Institute of Diabetes and Digestive and Kidney Diseases><National Institutes of Health><Nutrient><Obesity><Obesity associated disease><Obesity related disease><Output><Ovocyclin><Ovocylin><Pathway interactions><Peptides><Physiology><Play><Prebeta-Lipoproteins><Prevalence><Progynon><Property><Protein Binding><Response Elements><Risk><Risk Factors><Sex Differences><Sexual differences><Side><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Techniques><Testing><Therapeutic><Therapeutic Estradiol><Therapeutic Estrogen><Thesaurismosis><Tissues><Tracer><Triacylglycerol><Triglycerides><United States National Institutes of Health><VLDL><VLDL Lipoproteins><Very low density lipoprotein><Woman><adipogenesis><adiposity><alpha-Lipoprotein Cholesterol><alpha-Lipoproteins><atheromatosis><atheroprotection><atheroprotective><atherosclerotic disease><atherosclerotic heart disease><atherosclerotic vascular disease><attenuate><attenuates><biological signal transduction><bound protein><cardiac disease risk><cardiac disorder risk><cardiovascular disorder><cardiovascular risk><cardiovascular risk factor><coronary disorder><corpulence><diabetes><diabetic><diet-associated obesity><diet-induced obesity><diet-related obesity><estrogenic><fat metabolism><fatty acid oxidation><female outcomes><glucose metabolism><glycemic control><heart disease risk><heart disorder risk><hepatic body system><hepatic organ system><hepatic steatosis><hepatosteatosis><hyperglycemic><improved><innovate><innovation><innovative><insulin sensitivity><lipid biosynthesis><lipid metabolism><lipogenesis><male><men><metabolism disorder><mouse model><murine model><outcomes among females><outcomes among women><outcomes in females><outcomes in women><pathway><pre-clinical><preclinical><protective effect><protein activation><reverse cholesterol transport><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><therapeutic target><women's outcomes>