Metabolic diseases including obesity and type II diabetes are now global health concerns with a rising prevalence. Heat producing brown and beige fat have been proposed as targets for novel therapies to treat metabolic diseases based on animal models that have shown a role for these tissues in susceptibility to both obesity of diabetes. We have provocative preliminary data that show expression of the immune regulatory protein programmed death ligand 1 (PD-L1) within the brown fat of mice. We found that loss of function of PD- L1 led to changes in genes that regulate fat metabolism and mitochondrial biogenesis within the brown fat, and that these changes were associated with increased core body temperature and a surprising increased risk of weight gain when the mice were exposed to a high-fat diet. PD-L1 has achieved much clinical attention as a central component in enabling tumors to evade host immunity; immune therapy using antibodies that block PD- L1 or its receptor programmed death 1 (PD-1) are in clinical use to treat melanoma, lung and bladder cancer. The PD-1/PD-L1 pathway has been linked to metabolic changes in both tumors and the immune cells that respond to them, opening up the possibility that therapies targeting this pathway may directly influence the growth and replication of these cells. Thus a deeper understanding of the regulation of metabolism by PD-L1 is of substantial clinical interest. We hypothesize that PD-L1 directly regulates brown fat function, altering heat generation and modifying the risk of obesity. To understand the role of PD-L1 in brown fat more clearly, we propose first to generate a novel strain of mice with PD-L1 specifically removed in the brown fat cells themselves as prior experiments have been done with PD-L1 deficiency uniform across the whole mouse. These brown fat specific PD-L1 deficient animals are necessary to unequivocally demonstrate a direct role for PD-L1 in brown fat metabolism. Similarly, we will generate mice where the intracellular tail of PD-L1 has been removed only in brown fat; these animals will enable us to look for direct PD-L1 signaling in the regulation of brown fat. We will examine both susceptibility to obesity, and heat generation in these novel mouse strains; we will also use more sophisticated tracking of energy expenditure and feeding to understand the driving forces behind the elevated obesity risk in these animals. The second goal of this project is to characterize the changes in protein expression and metabolic intermediates in PD-L1 deficient brown fat to uncover the molecular mechanism by which PD-L1 regulates brown fat. These experiments will use immunoblotting and LC/MS based metabolomics to look at brown fat from total body PD-L1 deficient mice, as well as the novel brown fat specific PD-L1 deficient mice generated in this project. The long-term goal of this project is to elucidate the function of PD-L1 in regulation of metabolic disease, which should have implications not only for the regulation of body weight, but potentially for cancer immunotherapy as well.
The proposed research is relevant to public health because understanding the regulation of brown fat metabolism by PD-L1 may uncover important information about the regulation of susceptibility to obesity and diabetes with therapeutic implications for these highly prevalent metabolic diseases. Furthermore, because PD-L1 is already targeted by clinically approved anti-cancer drugs, new information about the regulation of metabolism by PD-L1 may have implications for cancer therapy as well. Thus, the proposed project is relevant to the NIH's mission to seek and apply knowledge to lengthen life and reduce illness.
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