Obesity is a chronic progressive disease that leads to several leading causes of death in United States, including heart disease, stroke, diabetes, and some types of cancer. Chronic inflammation has been recognized to promote the initiation and progression of obesity-related diseases. The NLRP3 inflammasome is one of the key mediators of obesity-related chronic inflammation. However, no effective and safe strategies have been developed to suppress the NLRP3 inflammasome and chronic inflammation in obesity. As such, Dr. Yu's long- term goal is to develop a new dietary strategy or therapeutic modality to suppress chronic inflammation in obesity and obesity-related diseases. As an initial step, this project will focus on chive leaf-derived exosome-like nanoparticles (CL-ELNs) because a pilot study suggested that CL-ELNs strongly inhibit NLRP3 inflammasome activation in macrophages, whereas the ELNs from nine other vegetables did not inhibit NLRP3 inflammasome activity. Building on this preliminary work, this project will test the central hypothesis that CL-ELNs contain active biomolecules that inhibit NLRP3 inflammasome activity and ameliorate metabolic inflammation in obesity. This hypothesis will be tested through two specific aims (SAs): SA1) identify the active biomolecules in CL-ELNs that inhibit NLRP3 inflammasome activity and SA2) evaluate effects of CL-ELNs on metabolic inflammation and metabolic health in obese animal models. To achieve SA1, the biomolecules in CL-ELNs will be examined to determine the active biomolecules critical to NLRP3 inflammasome inhibition. An `omics' analysis will be used to identify the biomolecules that are specifically enriched in CL-ELNs by comparing the `omics' profiles of CL-ELNs to other dietary ELNs that do not have inhibitory effects on the NLRP3 inflammasome. The biomolecules enriched in CL-ELNs will be tested individually for their effects on inflammasome activity. In SA2, C57BL/6J mice will be fed a high-fat diet to induce obesity, NLRP3 inflammasome activation, and chronic inflammation. The mice will be given orally CL-ELNs (treated group) or the solvent (control group). The NLRP3 inflammasome, chronic inflammation status, and metabolic health will be evaluated by measuring: NLRP3 inflammasome activity in adipose tissue macrophages; macrophage infiltration and inflammatory gene expression in metabolic tissues; fasting plasma glucose and insulin levels; glucose tolerance; insulin sensitivity; and plasma metabolite levels and metabolic gene expression in metabolic tissues. Successful completion of the proposed research will be the first step toward the translation of active biomolecules in CL-ELNs into novel therapies to suppress NLRP3 inflammasome and chronic inflammation in obesity. These outcomes are closely aligned with the thematic focus of the Nebraska Center for the Prevention of Obesity through Dietary Molecules (NPOD) ? to identify biological food-borne signals to prevent, treat, and cure obesity and related diseases ? given that CL-ELNs are one such food signal.
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