Adipose stem cells' niche in obesity

点击翻译按钮获取中文摘要

Obesity continues to escalate as a significant public health problem and as the leading preventable cause of death. Stark data from COVID19 pandemic shows obesity is an independent risk factor of severity with 33% mortality rate. Obesity per se is not fatal but is the major health risk factor promoting severe diseases including cardiovascular diseases, type 2 diabetes mellitus, and certain cancers. 42% of adult population in US is obese (CDC NCHS report 2020). Healthcare costs related to obesity account for greater than 10% of total US medical expenditures and has risen to $254 billion per year (1). Alarmingly 78% of the Veteran population is obese, a notably higher percent compared to civilian population(2). Adipose tissue is an important endocrine regulator of energy homeostasis and metabolism. During adipogenesis, the adipose stem cells (ASC) differentiate into adipocytes and replenish the body’s need for new adipocytes. Normal adiposity is exaggerated in obesity and is accompanied by adipocyte hyperplasia and hypertrophy. Previously this lab demonstrated that obesity changes the human adipose stem cells’ niche such that it promotes a microenvironment conducive to developing obesity-associated comorbidities. A significant finding was that the expression of long noncoding RNAs (lncRNAs) differed in the obese ASC compared to lean subjects which contributed to the aberrant metabolic processes, insulin resistance and chronic low-grade inflammation observed in obesity. Using an unbiased transcriptomic screening, this lab identified lncRNA GAS5 as an important regulatory gene that is depleted in human obese adipose tissue, ASC and mature adipocytes compared to lean. Prior research has demonstrated that GAS5 regulates insulin receptor and glucocorticoid receptor mediated pathways. However, the importance and impact of low GAS5 levels on the metabolic pathways in obese adipocytes has not yet been thoroughly investigated. Hence, it is hypothesized that low levels of GAS5 substantially contributes to the manifestation of comorbidities associated with obesity. Towards the overarching goal to determine if GAS5 supports healthy adipocytes, the proposal will evaluate the underlying mechanisms and role of GAS5 in human obese ASC and adipocytes using a multi-disciplinary approach including pre-clinical, physiological, cellular and biochemical experiments. Specific Aim 1: Determine the role of GAS5 in ASC and adipocytes: It is hypothesized that manipulating GAS5 levels will affect the metabolic health of ASC and adipocytes. GAS5 siRNA or over-expression plasmid will be used to evaluate the genetic and metabolic parameters pertaining to adipocyte health and function. Specific Aim 2: Elucidate molecular mechanisms regulated by GAS5 in obese adipocytes: GAS5 levels are low in ASC and adipose tissue in obesity. A small molecule that stabilizes GAS5 has been recently developed. It is hypothesized that stabilizing GAS5 levels could alleviate the metabolic stress and the project will use this compound as a molecular tool to determine the underlying molecular mechanisms with functional readouts. Specific Aim 3: Investigate the impact of GAS5 stabilization in vivo in an obese mouse model: The in vitro data shows that the small molecule targeting GAS5 increases IR levels, restores insulin signaling and regulates GR-target genes. This aim will systematically elucidate the physiological effects of stabilizing GAS5 with the novel therapeutic in a diet-induced obese mouse model. Overall, this project fills significant gaps in knowledge to understand the role of lncRNAs in the metabolic processes affecting adipose tissue in obesity in humans. Identification of GAS5 as a druggable RNA target in a metabolic disease has led to successfully develop a small molecule therapeutic that stabilizes GAS5 (a frontier in genomic medicine) with a high potential of promoting the metabolic health of ASC and adipocytes in obesity. This project will have a considerable impact to prevent or treat metabolic dysfunction associated with obesity, thus impeding the ascent of obesity as the most preventable cause of death.