权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The Role of Hypothalamic Slug in the Regulation of Leptin Sensitivity, Energy Balance, and Body Weight

下丘脑蛞蝓在瘦素敏感性、能量平衡和体重调节中的作用

基本信息

批准号：
9533545
负责人：
LIANGYOU RUI
金额：
$ 44.64万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9533545
关键词：
Adipose tissue Affect Blood Glucose Body Temperature Body Weight Brain Cells Data Diabetes Mellitus Eating Energy Metabolism Epigenetic Process Equilibrium Fatty Liver Fatty acid glycerol esters Genes Genetic Genomics Glucose Goals High Fat Diet Histone Acetylation Homeostasis Human Hypothalamic structure Impairment Insulin Resistance Knock-out Knockout Mice Lead Leptin Leptin resistance Link Lysine Maintenance Mediating Metabolic Metabolic Diseases Metabolism Methods Methylation Molecular Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Outcome Pathway interactions Predisposition Prevention Regulation Research Risk Factors Rodent Role SH2B gene Shapes Signal Transduction Slug protein Sympathetic Nervous System Temperature Testing Thermogenesis Time arm base cold temperature effective therapy energy balance epigenetic regulation feeding histone modification improved leptin receptor lipid metabolism nerve supply neurotransmission novel novel strategies nutrient metabolism obesogenic promoter receptor slug targeted treatment treatment strategy

项目摘要

Abstract (Description) Obesity is associated with leptin resistance, which limits the potential of leptin therapies. Leptin suppresses food intake and increases energy expenditure by activating its receptors (LepR) in the hypothalamic energy balance circuitry. The food intake arm of the energy balance circuitry has been extensively examined; however, the energy expenditure arm of the circuitry is poorly understood. Moreover, epigenetic reprograming of the hypothalamic energy expenditure circuits has not been explored in the setting of obesity. Leptin stimulates brown and beige adipose tissue thermogenesis, contributing to energy expenditure. Brown and beige fat are required for the maintenance of body temperature homeostasis in rodents, and they also protect against obesity through increasing energy expenditure in both rodents and humans. In preliminary studies, we found that high fat diet (HFD) feeding increases the level of hypothalamic Slug, a nuclear epigenetic factor. We demonstrated that Slug induces methylations and/or acetylation of histone 3 lysine 4 (H3K4) and H3K9, key forms of epigenetic remodeling, in several metabolic gene promoters. We showed that Slug suppresses the expression of Sh2b1, a positive regulator of leptin sensitivity, and stimulates the expression of SOCS3, a negative regulator of leptin signaling. Importantly, LepR+ cell-specific deletion of Slug in mice increases the sympathetic innervation of brown and beige fat, brown/beige fat thermogenesis, energy expenditure, and the body core temperature, but it does not affect food intake. LepR+ cell-specific Slug knockout mice resist HFD- induced leptin resistance, obesity, insulin resistance, and liver steatosis. Hence, we hypothesize that in obesity, aberrant hypothalamic Slug induces leptin resistance selectively in the energy expenditure arm by an epigenetic mechanism. Selective leptin resistance lowers the temperature setpoint, which in turn decreases the body core temperature and energy expenditure through lowering the sympathetic drive in brown/beige fat, thereby contributing to obesity progression. We will test these hypotheses in 3 Aims. Aim 1: Determine whether HFD feeding induces leptin resistance by inducing epigenetic reprograming of the hypothalamic Slug+LepR+ circuits via Slug. Aim 2: Determine whether HFD feeding impairs the leptin/temperature setpoint/SNS/brown/beige fat pathway by epigenetic mechanisms. Aim 3: Determine whether epigenetic regulation of the leptin/temperature setpoint/SNS/brown/beige fat pathway guides energy expenditure, body weight, and metabolism. This project is significant because it introduces the novel concepts of epigenetic reprograming of the hypothalamic energy balance circuits and regulation of obesity progression by the temperature setpoint and is expected to lead to new approaches in therapies targeting obesity.

文摘(描述)