Genetic regulators of vascular smooth muscle thermogenic differentiation

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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 by an increased level of the circulating lipokine 12,13-diHOME. The major cell type in adipose tissue is the adipocyte, and adipocytes that express Uncoupling protein 1 (Ucp1) are termed brown, beige, or recruitable thermogenic adipocytes. Thermogenic adipocytes can arise from two distinct lineages; the canonical lineage derived from mesenchymal preadipocytes that express platelet derived growth factor receptor alpha (Pdgfa), or a newly identified vascular smooth muscle (VSM) lineage that are recruited by cold challenge and are characterized bythe expression of Transient receptor potential cation channel subfamily V member 1 (Trpv1). Importantly, cells from the Trpv1+ VSM lineage express more UCP1 than other adipocytes. 12,13-diHOME is a putative lig and for Trpv1, however whether 12,13-diHOME drives the recruitment of thermogenic adipocytes by activating an adipogenic program is unknown. We propose the novel hypothesis that 12,13-diHOME activates Trpv1+ VSM thermogenic adipocyte precursor cells by signaling through Peroxisome proliferator-activated receptor alpha(Ppara), which has been reported to be downstream of Trpv1, to activate an adipogenic program that is normally suppressed in these cells. To test this hypothesis, we aim: 1) to determine the signaling pathway driving Trpv1+ VSM derived thermogenic adipogenesis; and 2) to identify the genes that suppress the adipogenic differentiation of Trpv1+ vascular smooth muscle cells. 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 treat these mice with 12,13 diHOME in combination with gain- and loss-of-function approaches to manipulate Ppara signaling and quantify the frequency of thermogenic adipocytes from the Trpv1+ VSM lineage. In the second aim, we will take an unbiased approach to assess the transcriptomic profile of thermogenic adipocytes from the Trpv1+ lineage and compare it to cells from the canonical lineage of adipocytes. This will be followed by in vivo CRISPR screening to systematically measure the effects of genetic loss-of-function for all mouse genes on Trpv1+ VSM adipogenesis. This project will be strongly supported by the COBRE Physiology Core (for cellular bioenergetics), the Histopathology and Microscopy Core (for tissue 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 perivascular adipose tissue (Lucy Liaw PhD), adipose tissue development (Patrick Seale PhD), and thermogenic fat (Shingo Kajiumura PhD). Determining the positive and negative regulators of Trpv1+ VSM thermogenic adipogenesis will provide new therapeutic strategies to treat obesity and metabolic syndrome.