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NIH grant 1R01DK146036-01A1: Investigating the Mechanistic Role of Brown Fat-derived Lipid Mediators and Their Analogs in Metabolic Health
Institute: {'code': 'DK', 'abbreviation': 'NIDDK', 'name': 'National Institute of Diabetes and Digestive and Kidney Diseases', 'admin_org_id': '12500020', 'admin_funding_url': ''}. PI: Kin Sing Stephen Lee. Award: $868285.
Start: 2026-08-26T00:00:00.
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.document fetched 2026-09-06 02:47