Investigating the Mechanistic Role of Brown Fat-derived Lipid Mediators and Their Analogs in Metabolic Health - Project Summary/Abstract Obesity contributes to metabolic disorders like type 2 diabetes, fatty liver, cardiovascular disease, and cancer. Brown adipose tissue (BAT) dissipates energy as heat and acts as an endocrine tissue. In humans, detectable BAT is associated with a lower prevalence of cardiometabolic diseases. While BAT is recognized for its energy-dissipating function, part of its beneficial effects arises from its secretory role. In recent years, bioactive lipids have been recognized as signaling molecules that mediate intercellular and inter-organ communication and regulate numerous physiological processes. Our lab, along with others, has identified several new bioactive lipids produced by BAT in response to physiological stimuli such as cold exposure or exercise training. Among these, the linoleic acid metabolite 12,13-diHOME has demonstrated multiple metabolic benefits, including the regulation of thermogenesis and fatty acid oxidation, as well as improvements in cardiac and endothelial functions. In humans, circulating levels of 12,13-diHOME are negatively correlated with BMI and various metabolic parameters, including circulating triglycerides and markers of hepatic damage. Individuals with heart disease also exhibit lower levels of 12,13-diHOME compared to those without heart issues. Therefore, this lipid mediator and its molecular mimics are promising candidates for combating obesity- related metabolic diseases. However, the signaling and molecular mechanisms through which 12,13-diHOME regulates metabolism remain to be elucidated. To address this knowledge gap, we conducted a GPCR screen and identified a promising GPCR as the potential receptor for 12,13-diHOME. This identification has opened a new pathway for understanding the mechanisms of 12,13-diHOME's action on metabolic regulation and supports the development of 12,13-diHOME mimics for pharmacological applications. In the proposed research, we will investigate the interactions between 12,13-diHOME and its target cells and assess their metabolic impact through in vitro co-culture studies and in vivo whole-body and conditional receptor knockout mouse models. We will determine the role of this ligand-receptor interaction in systemic metabolism. Finally, we will develop robust mimics with enhanced metabolic stability and bioavailability using innovative design strategies, high-throughput assays, and comprehensive pharmacokinetic evaluations. The proposed studies will deepen our understanding of the cellular and molecular mechanisms initiated by this lipid mediator and provide promising therapeutic approaches for treating obesity and related metabolic diseases.
