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Role of estrogens in hypothalamic inflammation and metabolic regulation.

雌激素在下丘脑炎症和代谢调节中的作用。

基本信息

批准号：
10482414
负责人：
Mauricio D Dorfman
金额：
$ 22.06万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-06 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10482414
关键词：
Ablation Affect Age American Animal Model Animals Anti-Inflammatory Agents Antiinflammatory Effect Area Attenuated Autopsy Biochemical Blood Vessels Body Composition Body Weight decreased Body mass index Brain Cardiovascular Diseases Cells Chronic Disease Data Development Diet Eating Encephalitis Energy Metabolism Epidemic Estradiol Estrogen Antagonists Estrogen Metabolism Estrogen Receptor alpha Estrogen Receptor beta Estrogen Replacement Therapy Estrogen Therapy Estrogens Female Future Genetic Gliosis Gonadal Steroid Hormones Health High Fat Diet Human Hyperphagia Hypertension Hypothalamic structure Immune Infiltration Inflammation Inflammatory Inflammatory Response Knockout Mice Link Malignant Neoplasms Mediating Mediator of activation protein Menopause Metabolic Metabolic Diseases Microglia Modeling Mus Neuroglia Neuronal Injury Neurons Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity Ovariectomy Overweight Pharmacology Predisposition Premenopause Prevalence Primary Prevention Property Public Health Regulation Research Resistance Risk Risk Factors Rodent Rodent Model Role Selective Estrogen Receptor Modulators Signal Transduction Testing Therapeutic Intervention Therapeutic Trials Tissues Visceral Weight Gain Woman blood glucose regulation cancer risk cell type cellular targeting comorbidity deprivation diet-induced obesity dietary effective therapy energy balance excessive weight gain feeding in vivo macrophage male men metabolic rate mouse model novel pre-clinical reduced food intake reproductive response sexual dimorphism side effect stroke risk trend western diet

项目摘要

Project Summary Obesity is a grave public health threat since it greatly increases the risk of highly morbid chronic diseases including type 2 diabetes, hypertension, cardiovascular disease, and many cancers. Currently, over 60 percent of Americans are overweight or obese, and the lack of effective therapies available for weight reduction make it imperative to focus on unraveling the mechanisms underlying obesity and its associated metabolic disorders. This proposal focuses on brain mechanisms by which sex steroids protect from obesity and its associated metabolic diseases. Premenopausal women have a lower rate of metabolic disorders than men of the same age, but this trend reverses after menopause with increase of weight gain, accumulation of visceral adiposity and increase in associated comorbidities. While estrogen replacement therapy can reverse many of these menopausal changes, the increased cancer and stroke risks associated with this therapy preclude its use for primary prevention, creating a demand for understanding the mechanisms by which estrogen protects from obesity and its associated metabolic risks. Growing evidence suggests that obesity is associated with hypothalamic neuronal injury, inflammation, and reactive gliosis, characterized by activation of local microglia (the macrophage of the brain). Rodent studies have demonstrated that reducing hypothalamic inflammation and microglial activation limits weight gain and the metabolic complications of diet-induced obesity. Similarly, estrogen reduces food intake, increases energy expenditure, and can potently suppress brain inflammation. In addition, female mice are more resistant to diet-associated microglial activation and weight gain, suggesting a potential link between estrogen and microglial signaling. Indeed, our preliminary observations demonstrate that estrogen deficiency increases signs of diet-induced hypothalamic inflammation and gliosis. These findings support studies proposed in Specific Aim 1 to use animal models with ablation of microglial inflammation to determine whether hypothalamic gliosis is required for Western-type diet and estrogen deficiency to synergistically predispose to obesity and its associated metabolic complications. Additionally, we have developed mouse models with microglia-specific deletion of either estrogen receptor alpha (ERα) or estrogen receptor beta (ERβ) to determine the requirement of microglial estrogen signaling to protect from diet-induced obesity (Aim 2). The proposed studies will advance our understanding of how estrogen deficiency confers metabolic risk and test a novel model of estrogen- mediated metabolic regulation through action in microglia. More broadly, this proposal will provide new central mechanisms to explain the higher metabolic risk observed in women with low estrogen levels, and new microglial targets for preclinical therapeutic trials to reduce this risk.

项目总结