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Principal Investigator: Rudolph c Johnson
Organization: JAMES A. HALEY VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
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.
Terms: <21+ years old><Adipocytes><Adipose Cell><Adipose tissue><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Affect><Afghanistan><Autoregulation><BMI><BMI percentile><BMI z-score><Biochemical><Biology><Blood Vessels><Body mass index><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><CV-19><Cancers><Cardiovascular Diseases><Caring><Cause of Death><Cell Body><Cells><Chronic><Chronic Disease><Chronic Illness><Clinical><Core Facility><Coronavirus Infectious Disease 2019><Data><Death Rate><Department of Defense><Development><Diabetes Mellitus><Differentiation in cell culture><Disease><Disorder><Endocrine><Evaluation><Fat Cells><Fatality rate><Fatty Tissue><Functional RNA><Genes><Genetic><Genomic medicine><Glucocorticoid Receptor><Goals><Guidelines><Gulf War><Health><Health Care Costs><Health Costs><Health Expenditures><Healthcare Costs><Homeostasis><Human><Humulin R><Hyperplasia><Hyperplastic><Hypertrophy><In Vitro><In vitro cell differentiation><Inflammation><Inflammatory><Insulin><Insulin Receptor><Insulin Receptor Protein-Tyrosine Kinase><Insulin Resistance><Insulin-Dependent Tyrosine Protein Kinase><Intermediary Metabolism><Investigators><Iraq><Ketosis-Resistant Diabetes Mellitus><Knowledge><Leanness><Lipocytes><Malignant Neoplasms><Malignant Tumor><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Pathway><Metabolic Processes><Metabolic dysfunction><Metabolic stress><Metabolic syndrome><Metabolism><Mice><Mice Mammals><Modern Man><Molecular><Morbid Obesity><Murine><Mus><NCHS><NIDDM><National Center for Health Statistics><Non-Coding><Non-Coding RNA><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Non-Polyadenylated RNA><Non-sense Mediated Decay><Non-translated RNA><Noncoding RNA><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nonsense-Mediated Decay><Nontranslated RNA><Novolin R><Obese Mice><Obesity><Operation Desert Shield><Operation Desert Storm><Over weight><Overweight><Pathology><Pathway interactions><Pattern><Physiologic><Physiological><Physiological Homeostasis><Plasmids><Population><Public Health><Quetelet index><RNA><RNA Gene Products><Receptor Protein><Regular Insulin><Regulator Genes><Reporting><Research><Research Personnel><Researchers><Ribonucleic Acid><Risk Factors><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe obesity><Severities><Short interfering RNA><Slow-Onset Diabetes Mellitus><Small Interfering RNA><Stable Diabetes Mellitus><T2 DM><T2D><T2DM><Thesaurismosis><Thinness><Tissue Differentiation><Transcriptional Regulatory Elements><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><United States Department of Veterans Affairs><United States National Center for Health Statistics><United States Veterans Administration><Untranslated RNA><Veterans><Veterans Administration><Veterans Affairs><Woman><Work><adipogenesis><adipose><adipose derived stem cell><adipose progenitor><adipose stem cell><adiposity><adult onset diabetes><adulthood><beneficiary><cardiovascular disorder><chronic disorder><co-morbid><co-morbidity><comorbidity><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus infectious disease-19><corpulence><developmental><diabetes><diet-associated obesity><diet-induced obesity><diet-related obesity><differentiation in culture><differentiation in vitro><experience><experiment><experimental research><experimental study><experiments><extreme obesity><frontier><gas 5 RNA><gas5 RNA><genetic make-up><genetic makeup><growth arrest gas-5 gene product><growth arrest specific transcript 5><health care expenditure><healthcare expenditure><in vitro cellular differentiation><in vivo><individual patient><insulin resistant><insulin signaling><insulin tolerance><interdisciplinary approach><ketosis resistant diabetes><lipid biosynthesis><lipogenesis><malignancy><maturity onset diabetes><medical expenditure><metabolism disorder><military veteran><mortality><mortality rate><mortality ratio><mouse model><multidisciplinary approach><murine model><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><noncoding><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ob/ob mouse><obese individuals><obese patients><obese people><obese person><obese population><obese subjects><obesity intervention><obesity therapy><obesity treatment><overexpress><overexpression><pathway><patients with obesity><pre-clinical><preclinical><prevent><preventing><progenitor cell differentiation><progenitor cell markers><progenitor cell niche><progenitor differentiation><progenitor markers><progenitor niche><progenitor stem cell markers><receptor><regulatory gene><screening><screenings><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><siRNA><small molecule><small molecule therapeutics><social role><statistics><stem and progenitor cell niche><stem and progenitor differentiation><stem cell biomarkers><stem cell differentiation><stem cell markers><stem cell niche><tool><trans acting element><transcriptomics><type 2 DM><type II DM><type two diabetes><vascular><veteran population><white adipose tissue><yellow adipose tissue>