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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.

项目总结: