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A novel adipokine suppresses leptin signaling and promotes obesity

一种新型脂肪因子抑制瘦素信号传导并促进肥胖

基本信息

批准号：
10327290
负责人：
Yong-Xu Wang
金额：
$ 41.88万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10327290
关键词：
Address Adipocytes Adipose tissue Appetite Stimulants Attenuated Binding Binding Proteins Bioinformatics Blood - brain barrier anatomy Blood Circulation Blood Glucose Body Weight Brain Stem Brown Fat Cell surface Communication Critical Pathways Defect Development Diabetes Mellitus Eating Endocrine Endocrine Glands Fasting Fatty acid glycerol esters Genes Goals Hepatic Homeostasis Hormonal Hormones Human Hyperphagia Hypothalamic structure Impairment In Vitro Injections Investigation Knockout Mice Lead Leptin Leptin resistance Liver Medical Metabolic Diseases Modeling Morbid Obesity Mus Neuraxis Non-Insulin-Dependent Diabetes Mellitus Nutritional status Obesity Pathway interactions Patients Peptides Peripheral Phenotype Proteins Receptor Activation Recombinants Resistance Role Signal Pathway Signal Transduction Signal Transduction Pathway Tissues Transgenic Mice Transplantation Type 2 diabetic Viral Wild Type Mouse adipokines blood glucose regulation diabetic patient energy balance experimental study feeding functional loss gain of function improved in vivo innovation knock-down leptin receptor loss of function mouse model novel novel therapeutics obese patients response selective expression subcutaneous therapeutic target

项目摘要

Our long-range goal is to understand signal transduction pathways underlying energy homeostasis and how their alterations contribute to obesity and metabolic diseases. The leptin signaling pathway is considered to be the most critical anorexigenic pathway in the control of food intake and body weight. Moreover, this pathway has been demonstrated to improve glucose homeostasis independently of its effects on body weight and food intake. However, obese patients, and type 2 diabetic patients who are commonly obese, response poorly to exogenous leptin treatment, and are thus considered to be leptin resistant. Therefore, elucidating the underlying mechanisms of leptin resistance is of great medical importance. To date, whether peripheral tissues produce endocrine factors to attenuate leptin signaling remains to be explored. We identified a previously uncharacterized, adipose tissue-selectively expressed 8 kD adipokine we called Batotin. We found that this adipokine binds to leptin receptor and suppresses leptin signaling. Remarkably, transgenic mice expressing Batotin in adipose tissue are hyperphagia and morbidly obese, and have elevated blood glucose level independent of obesity. These results lead to a model that secreted Batotin from peripheral tissue acts as an orexigenic peptide in an endocrine manner to suppress leptin signaling. In Aim 1, we will investigate in detail how Batotin suppresses leptin signaling. In Aim 2, we will use gain-of-function mouse models to investigate the function and mechanism of Batotin. In Aim 3, we will study loss-of-function mouse models.

我们的长期目标是了解能量稳态的信号转导途径，以及它们的改变如何导致肥胖和代谢疾病。瘦素信号通路被认为是控制食物摄入和体重的最关键的促瘦素途径。此外，该途径已被证明可改善葡萄糖稳态，而与其对体重和食物摄入的影响无关。然而，肥胖患者和通常肥胖的2型糖尿病患者对外源性瘦素治疗反应不佳，因此被认为是瘦素抵抗性的。因此，阐明瘦素抵抗的潜在机制具有重要的医学意义。迄今为止，外周组织是否产生内分泌因子来减弱瘦素信号传导仍有待探索。我们发现了一个以前未表征的，脂肪组织选择性表达的8 kD脂肪因子，我们称之为Batotin。我们发现这种脂肪因子与瘦素受体结合并抑制瘦素信号传导。值得注意的是，在脂肪组织中表达巴托汀的转基因小鼠是暴食和病态肥胖的，并且具有与肥胖无关的升高的血糖水平。这些结果导致从外周组织分泌的Batotin以内分泌方式作为食欲肽以抑制瘦素信号传导的模型。在目标1中，我们将详细研究Batotin如何抑制瘦素信号传导。目的二：利用功能获得性小鼠模型研究巴托汀的作用机制。在目标3中，我们将研究功能丧失小鼠模型。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A brown fat-enriched adipokine Adissp controls adipose thermogenesis and glucose homeostasis.

DOI：
10.1038/s41467-022-35335-w
发表时间：
2022-12-10
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Chen, Qingbo;Huang, Lei;Pan, Dongning;Hu, Kai;Li, Rui;Friedline, Randall H.;Kim, Jason K.;Zhu, Lihua Julie;Guertin, David A.;Wang, Yong-Xu
通讯作者：
Wang, Yong-Xu

The KRAB Domain-Containing Protein ZFP961 Represses Adipose Thermogenesis and Energy Expenditure through Interaction with PPARα.