Obesity is a global pandemic with enormous financial burden and health cost due both to the increasingly large proportion of the population who are overweight or obese and the broad range of associated sequelae such as cardiovascular disease, type 2 diabetes, and some cancers. The development of strategies to prevent or treat human obesity is therefore extremely important. Recently, a great deal of interest has been centered on the metabolic capacity of brown fat in humans and the discovery and standardization of treatment regiments that activate brown fat thermogenesis and expend energy. In order to activate brown adipose tissue, several research strategies have been pursued, including both pharmacological interventions and physiologic cold exposure. Unfortunately, the thermogenic effect of many compounds that occurs in mice is not observed in humans, although recently B-3 adrenergic agonists that activate human BAT have been recently been reported. To this end, an innovative approach is proposed wherein I plan to investigate bioactive lipids as a novel class of circulating factors with potential pro-thermogenic effects in brown adipose tissue. Recently, studies have demonstrated that lipid molecules can act as hormones secreted to act as signaling molecules in distal organs. These lipids promote insulin sensitivity and glucose tolerance through their interaction with proteins located on the cell membrane. Conventionally, lipids have not been considered as potential endocrine factors. With this in mind, I have investigated the potential of lipids to act as secreted molecules that mediate, at least in part, the physiologic response to cold challenge. Preliminary studies have made the novel discovery that the lipid one specific target lipid species increases in circulation of mice and humans that are exposed to cold and further, systemic injection of this lipid can increase thermogenesis. This approach is innovative because lipid molecules have not been previously reported as secreted mediators of thermogenesis. In this proposal, I will systematically determine the effect of this lipid on whole body energy metabolism and determine the underlying molecular mechanisms that mediate enhanced thermogenesis after treatment with our target lipid. These results could a have significant impact in the development of treatments for obesity and cardiovascular disease.
Understanding the lipidomics of thermogenic adipose tissue relates to human health because the results would both increase our understanding of lipid metabolism during thermogenesis and suggest novel therapeutic pathways to regulate this processes to enhance energy expenditure for the treatment of obesity and its related disorders in humans. In generating preliminary data to support this proposal, I have measured the concentration of approximately 3,000 lipids during thermogenesis in humans and confirmed signatures in murine models to identify a specific lipid that may activate thermogenesis and a pathway that is augmented in thermogenic adipose tissue. By completing the studies in this proposal, I hope to determine the mechanism of action of this thermogenic lipid in brown adipose tissue.
| Lynes, Matthew D; Shamsi, Farnaz; Sustarsic, Elahu Gosney et al. (2018) Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism. Cell Rep 24:781-790 |
| Bartelt, Alexander; Widenmaier, Scott B; Schlein, Christian et al. (2018) Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity. Nat Med 24:292-303 |
| Stanford, Kristin I; Lynes, Matthew D; Takahashi, Hirokazu et al. (2018) 12,13-diHOME: An Exercise-Induced Lipokine that Increases Skeletal Muscle Fatty Acid Uptake. Cell Metab 27:1111-1120.e3 |
| Ramirez, Alfred K; Lynes, Matthew D; Shamsi, Farnaz et al. (2017) Integrating Extracellular Flux Measurements and Genome-Scale Modeling Reveals Differences between Brown and White Adipocytes. Cell Rep 21:3040-3048 |
| Lynes, Matthew D; Leiria, Luiz O; Lundh, Morten et al. (2017) The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat Med 23:631-637 |
