Genetics regulators of vascular smooth muscle thermogenic differentiation

血管平滑肌产热分化的遗传调控因子（M. Lynes，项目负责人）

Genetic regulators of vascular smooth muscle thermogenic differentiation (M. Lynes, Project Lead) Obesity and metabolic syndrome are major public health burdens and occur when fat mass increases, leading to dysfunction in adipose tissue. Obesity is negatively associated with the presence of thermogenic brown adipose tissue (BAT), which can be detected in humans and mice exposed to cold temperatures. The major cell type in adipose tissue is the adipocyte, and in addition to white adipocytes, cells that express Uncoupling protein 1 (Ucp1) are termed brown, beige, or recruitable thermogenic adipocytes. Adipocytes can arise from two distinct lineages; the canonical lineage derived from mesenchymal preadipocytes that express platelet derived growth factor receptor alpha (Pdgfra), or a newly identified vascular smooth muscle (VSM) lineage that are recruited by cold challenge and are characterized by the expression of Transient receptor potential cation channel subfamily V member 1 (Trpv1). Importantly, cells from the Trpv1+ VSM lineage can express more UCP1 than other adipocytes, supporting the premise that they are a distinct cell type. We propose the novel hypothesis that Trpv1+ VSM derived adipocytes are a unique type of fat cell that can regulate whole body metabolism. To test this hypothesis, we aim to: 1) inhibit adipogenesis of Trpv1+ VSM derived adipocytes and determine the impact on systemic metabolism; and 2) utilize the unique proteomic signature Trpv1+ VSM derived adipocytes to identify functional networks for further study. We will utilize a Trpv1 lineage tracing mouse model to track the contribution of Trpv1+ VSM cells to thermogenic adipocytes. In the first aim, we will block Ppara signaling using CRISPR-mediated gene editing specifically in Trpv1+ cells and quantify the frequency of adipocytes from the Trpv1+ VSM lineage as well as the effect on glucose and triglyceride metabolism. In the second aim, we will take an unbiased approach to identify the proteome of adipocytes from the Trpv1+ lineage and compare it to cells from the canonical Pdgfra lineage of adipocytes. Proteins that are identified can then be edited using our Trpv1 lineage tracing model to determine their impact on adipogenesis and systemic metabolism. This project will be strongly supported by the COBRE Physiology Core (for cellular bioenergetics), the Histopathology and Microscopy Core (for tissue processing, staining, analysis, and confocal microscopy), and the Proteomics and Lipidomics Core (lipid and protein profiling). This innovative project is led by a new junior investigator, Dr. Matthew Lynes, who will be supported by outstanding expert mentors in the fields of adipose tissue development (Patrick Seale PhD), thermogenic fat (Shingo Kajimura PhD) and mouse genetics (Joseph Nadeau PhD). Determining the role of Trpv1+ VSM derived adipocytes in systemic metabolism as well as their unique protein signature could provide new targets and strategies to treat obesity and metabolic syndrome.