SUN-544 Immunologic Effects of GLP-1 Activation in Obese Adipose Tissue

Abstract Background: Obesity is associated with systemic inflammation which is thought to stem, in part, from adipose tissue (AT). Obese AT is characterized by infiltration of pro-inflammatory T cells that promote macrophage activation and inflammation. GLP-1 has been shown to have anti-inflammatory effects in previous studies. We hypothesized that promotion of GLP-1 signaling with liraglutide or sitagliptin would reduce inflammation in association with an increase in the number of anti-inflammatory invariant natural killer T cells (iNKTs), group 2 innate lymphoid cell (ILC2s) and regulatory T cells (Treg) in blood and AT. Methods: Obese adults with pre-diabetes were randomized to pharmacologic treatment resulting in increased GLP-1 signaling (liraglutide or sitagliptin, N=8), or hypocaloric diet (N=3). This ongoing study is blinded, so the effects of liraglutide and sitagliptin are combined in analyses and referred to as “drug”. Subcutaneous abdominal AT and peripheral blood mononuclear cells (PBMCs) were collected at baseline (“pre”) and after 12 weeks of therapy (“post”). Phenotypic marker expression of blood and AT T cells were characterized by flow cytometry. Whole AT inflammatory gene expression in the pre and post groups was assessed by Nanostring. Results: Using the Nanostring inflammation panel, we found that a number of pro-inflammatory genes were significantly downregulated in whole AT after treatment with drug, including CD163, CD86, CCR1, MCP-2, and MCP-4. Blood ILC2s were significantly decreased with drug treatment (pre 3.95%±3.05, post 1.71% ±1.65, p=0.01), but not diet (pre 2.17% ±1.91, post 1.46% ±1.68, p=0.18). We did not detect a change in Treg numbers after treatment with either diet (pre 5.78% ±1.91, post 6.09% ±1.50, p=0.29) or drug (pre 6.49% ±2.29, post 5.94% ±2.15, p=0.12). Similarly, no difference in blood iNKT numbers was detected after diet (pre 0.063% ±0.044, post 0.082% ±0.049, p=0.11) or drug (pre 0.077% ±0.106, post 0.091% ±0.130, p=0.67). As observed in the PBMCs, adipose ILC2s were decreased after drug (pre 2.04% ±1.67, post 1.32% ±1.58, p=0.07, N=4). We did not detect a change in AT Treg and iNKT numbers (Treg pre 9.24% ±5.36, post 6.23% ±1.55, p=0.14; iNKT pre 0.12% ±0.08, post 0.09% ±0.05, p=0.47, N=4). Conclusions: In a small pilot study of obese pre-diabetic patients treated with drugs that activate GLP-1 signaling (liraglutide or sitagliptin) or hypocaloric diet, global transcriptional analysis of whole AT suggested decreased inflammation with drug therapy. However, we found decreased percentages of ILC2 cells (considered anti-inflammatory in adipose) in both blood and AT after drug treatment. Future experiments will further characterize the function of these cell types, and evaluate other immune subsets in PBMC and AT that may be responsible for decreasing inflammation.