Ciliary signaling mechanisms regulating white adipose tissue expansion

调节白色脂肪组织扩张的纤毛信号机制

基本信息

批准号：
10670408
负责人：
Keren Hilgendorf
金额：
$ 38.5万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-22 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670408
关键词：
Ablation Adipocytes Adipose tissue Adult Affect Alstrom syndrome Architecture Bardet-Biedl Syndrome Biological Body mass index Calories Cells Chromatin Cilia Cyclic AMP DNA Sequence Alteration Data Defect Development Diabetes Mellitus Docosahexaenoic Acids Equilibrium Fatty acid glycerol esters Female Functional disorder Genes Genetic Genetic Transcription Goals Health Human Human Genetics Hyperplasia Hypertrophy Impairment Inflammation Insulin Resistance Lead Ligands Link Metabolic Metabolic syndrome Molecular Monounsaturated Fatty Acids Morphology Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Nutrient Obese Mice Obesity Omega-3 Fatty Acids Organelles Overweight Pathogenesis Pathogenicity Patients Polyunsaturated Fatty Acids Proteins Public Health Publishing Research Signal Pathway Signal Transduction Techniques Thinness Tissue Differentiation Tissue Expansion Tissues chromatin remodeling ciliopathy comorbidity experimental study glucose metabolism in vivo innovation lipid biosynthesis lipid metabolism male mouse model novel pandemic disease receptor response tool trafficking

项目摘要

Project summary: More than 70% of adults in the USA are obese or overweight, and comorbidities, such as diabetes, pose a significant challenge to public health. In response to excess nutrients, white adipose tissue expands by both hypertrophy and de novo adipogenesis. Excessive hypertrophy is linked to insulin resistance, while mechanisms that promote adipogenesis can limit the pathogenic consequences of obesity. We recently discovered that pre- adipocytes express an antenna-like signaling organelle called the primary cilium, and that primary cilia are required for in vivo adipogenesis. We propose that primary cilia function as signaling hubs in pre-adipocytes, regulating their adipogenic potential, and hence, how white adipose tissue expands in response to caloric imbalance. Remarkably, we recently discovered that pre-adipocytes isolated from obese human and murine white adipose tissue have both fewer and shorter cilia compared to lean pre-adipocytes. To elucidate the functional importance of ciliary signaling in directing how white adipose tissue expands, we propose the following two aims: (Aim 1) Investigate how obesity affects pre-adipocyte ciliation and ciliary signaling. Pre-adipocytes in obese white adipose tissue are known to differentiate poorly due to a cell-intrinsic defect that decreases their adipogenic potential. This contributes to adipocyte hypertrophy, inflammation, and tissue dysfunction. We propose that the obese white adipose tissue microenvironment promotes pathogenic loss of pre-adipocyte primary cilia. This loss results in impairment of ciliary, pro-adipogenic signaling and decreased adipogenic potential, leading to hypertrophic expansion of white adipose tissue and contributing to impairments in glucose and lipid metabolism. Using a combination of molecular and cell biological techniques and mouse models, we will define the adipogenic signaling defects governed by obesity-induced ciliary shortening and loss, as well as the underlying mechanism. (Aim 2) Determine how human genetic mutations in ciliary genes lead to obesity and diabetes. Two ciliopathies are linked to obesity in patients, but the mutations drive opposing effects with regard to metabolic health. Both ciliopathy mutations alter the trafficking of ciliary cargo into and out of the primary cilium. We propose that these alterations modulate the composition of ciliary signaling pathways, altering the adipogenic potential of pre-adipocytes and how white adipose tissue expands. Together, experiments proposed in the two aims will establish the functional importance of pre-adipocyte cilia to white adipose tissue expansion. The proposed research constitutes a completely novel and innovative approach to identifying mechanisms underlying the loss of adipogenic potential of obese pre-adipocytes that drives pathogenesis.

项目摘要：美国超过70％的成年人是肥胖或超重，合并症（例如糖尿病）对公共卫生的重大挑战。为了响应多余的营养，白色脂肪组织都会扩展肥大和从头脂肪生成。过度肥大与胰岛素抵抗有关，而机制促进脂肪形成可以限制肥胖的致病后果。我们最近发现脂肪细胞表达一种天线样信号传导细胞器，称为原发性纤毛，原代纤毛是体内脂肪形成所必需的。我们提出，一级纤毛在前脂肪细胞中充当信号枢纽，调节其成脂潜力，因此，白色脂肪组织如何响应热量不平衡。值得注意的是，我们最近发现，从肥胖的人和鼠类中分离出的前脂肪细胞与瘦脂肪细胞相比，白色脂肪组织的纤毛较少和较短。阐明睫状信号在指导白脂肪组织如何扩展时的功能重要性，我们提出以下两个目的：（目标1）研究肥胖是如何影响前脂肪细胞纤毛和纤毛信号传导的。前脂肪细胞肥胖的白色脂肪组织已知由于细胞中性缺陷而降低了它们成脂潜力。这有助于脂肪细胞肥大，炎症和组织功能障碍。我们提出肥胖的白脂肪组织微环境促进了脂肪细胞的致病性丧失原发性纤毛。这种损失导致睫状，促脂性信号传导和脂肪生成降低。潜力，导致白脂肪组织的肥厚性膨胀，并导致葡萄糖损害和脂质代谢。使用分子和细胞生物技术和小鼠模型的组合，我们将定义由肥胖诱导的睫毛缩短和损失和损失以及基本机制。（目标2）确定睫状基因中的人类遗传突变如何导致肥胖和糖尿病。两种纤毛病与患者的肥胖有关，但这些突变引起了相反的影响代谢健康。两种纤毛病变突变都会改变纤毛货物进入和流入主要纤毛。我们建议这些改变调节了睫状信号通路的组成，从而改变了脂肪细胞的成脂潜力以及白脂肪组织如何扩展。共同提出了实验在这两个目标中，将确定脂肪细胞前纤毛对白脂肪组织扩张的功能重要性。拟议的研究构成了一种完全新颖而创新的方法来识别机制肥胖前脂肪细胞的成脂潜力丧失的基础，从而驱动发病机理。