Sunday, May 11, 2025
5/11/2025
The Renin-Angiotensin System in Air Pollution-Mediated Exacerbation of Obesity. - Significance. Exposure to traffic-generated particulate matter (PM), a significant source of ambient air pollution, is associated with adverse health outcomes, including metabolic disorder and obesity, rates of which are increasing in children and adults worldwide. However, the pathways involved in promoting an obese adipose phenotype resulting from PM exposure are not fully understood. An “unhealthy” gut microbiome and increased tissue-specific adipose renin-angiotensin system (RAS) signaling are both associated with obesity; however, the signaling pathways that link these two factors have not been fully characterized, especially related to environmental PM exposure. Thus, whether PM exposure mediates abnormal gut microbiota profiles that promote alterations in short-chain fatty acid (SCFA) and glucagon-like peptide (GLP)-1 signaling in the intestines will be determined. Elucidating the role of GLP-1 on tissue level RAS signaling in adipocytes may provide novel targets for future therapies for susceptible individuals living in regions with high urban air pollution levels. Innovation. The proposed experiments will analyze the cross-talk between SCFA, GLP-1, and RAS signaling in adipose tissue to determine whether inhalation exposure to diesel engine exhaust PM (DEP) results in altered gut microbiome profiles associated with deregulation of GLP-1-mediated RAS signaling and subsequent alterations in the adipose structure and metabolic/endocrine function associated with obesity. Importantly, these analyses will be conducted in tissues derived from male and female C57BL/6 mice, using characterized DEP, and appropriate pharmaceutical interventions (GLP-1 agonist, probiotics), to simulate exposure scenarios and underlying pathophysiologic states similar to that in the human population. Adipocyte cell culture will be used to further investigate the mechanism and 16S Next-Generation Sequencing, NanoString, and Multiplex methodologies to reveal alterations in the gut microbiome and metabolic/endocrine pathways involved in obesity. Specific Aims. The preliminary data shows that exposure to mixed vehicle engine emissions results in weight gain, adipocyte hypertrophy, and elevated adipose tissue level RAS in male C57BL/6 mice; however, the role of DEP has not been investigated as a contributing causative component in these outcomes. Thus, the hypothesis that inhalational DEP exposure promotes obesogenic profiles in adipose tissue through deregulation of GLP-1 – Ang II signaling will be investigated. In Aim 1, the outcome of inhaled DEP on gut microbiota profiles and SCFA signaling in regulating GLP-1 expression and RAS-mediated adipocyte hypertrophy and adipokine signaling will be analyzed C57BL/6 male and female mice using a probiotic treatment. DEP-mediated alterations in systemic metabolic and obesogenic gene expression pathways will also be assessed. In Aim 2, it will be determined whether DEP exposure mediates alterations in GLP-1 on adipocyte RAS signaling and subsequent lipid accumulation through GLP-1 agonist treatment (in vivo), and also GLP-1 agonist vs. siRNA knockdown of local GLP-1 receptor signaling (in vitro) in adipocyte cell culture treated with plasma from our study animals.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).