Type 2 diabetes (T2D) and obesity have emerged as major public health crises. These conditions increase the risk of cardiovascular diseases and cause microvascular dysfunction. Patients with T2D also show deficits in wound healing and tissue repair. Although the mechanisms leading to T2D are not well understood, recent work has shown that the states of diabetes and obesity are associated with low-grade chronic inflammation, which triggers and sustains insulin resistance in target tissues. This project is to test the hypothesis that chronic inflammation in obesity and diabetes is sustained in part due to the failure of pro-resolving pathways. This hypothesis predicts that innate immune responses activated in obesity and diabetes fail to resolve leading to chronic inflammation and insulin resistance. It also predicts that restoration of endogenous pro-resolving mediators should extinguish inflammation and restore insulin sensitivity.
The specific aims of this project are to: (1) Define changes in resolution of inflammation during diabetes and obesity;(2) Determine whether restoring resolution will diminish inflammation and insulin resistance;and (3) Identify the mechanism by which promotion of resolution affects insulin resistance. To accomplish these aims we will examine the time course of the development and the resolution of acute inflammation. We will measure changes in pro-resolving lipid mediators by a mass-spectrometry-based lipidomic approach, establish the temporal relationship between changes in lipid mediator synthesis and insulin resistance, and identify the mechanisms by which diabetes and obesity affect the biosynthesis of pro-resolution mediators. To assess the functional significance of the changes in resolution in diabetes and obesity, we will test whether treatment with resolvin D1 (RvD1) will correct the resolution defect and improve glucose tolerance, systemic insulin resistance, and wound healing in high-fat fed and db/db mice. We will determine how RvD1 affects vascular inflammation and adipose-tissue macrophage phenotype. To delineate the mechanism of action, we will examine whether obesity and diabetes affects the expression and function of the RvD1-receptor, Frp2, in macrophages and adipose tissue, and whether Frp2 deletion will abolish the pro-resolving effects of RvD1, as well as its ability to diminish chronic inflammation, insulin resistance, and promote wound healing. To distinguish between the effect of RvD1 on macrophages and adipocytes, and as a gain-of-function test of our hypothesis, we will test whether myeloid- specific overexpression of human FPR2 will enhance resolution of inflammation in diabetes and promote the pro-resolving actions of RvD1. We will identify the mechanisms by which binding of RvD1 to Fpr2 promotes macrophage phagocytosis. Results of this project will provide new knowledge about the processes that sustain chronic adipose tissue inflammation and promote insulin resistance in diabetes and obesity, and could lead to the development of an entirely new approach for the treatment of insulin resistance and wound healing in diabetes and obesity.

Public Health Relevance

This project will provide a new understanding of the mechanisms that contribute to chronic inflammation in diabetes and obesity and will provide new avenues for treating insulin resistance in diabetes and obesity. These results could also be developed as an adjunct treatment for promoting resolution of inflammation and wound healing in diabetics.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106173-02
Application #
8308369
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Tolunay, Eser
Project Start
2011-08-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$375,000
Indirect Cost
$125,000
Name
University of Louisville
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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Wu, Bian; Werlin, Evan C; Chen, Mian et al. (2018) Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model. J Vasc Surg 68:188S-200S.e4
Chatterjee, Anuran; Komshian, Sevan; Sansbury, Brian E et al. (2017) Biosynthesis of proresolving lipid mediators by vascular cells and tissues. FASEB J 31:3393-3402
Cai, Bishuang; Thorp, Edward B; Doran, Amanda C et al. (2017) MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis. J Clin Invest 127:564-568
Fredman, Gabrielle; Spite, Matthew (2017) Specialized pro-resolving mediators in cardiovascular diseases. Mol Aspects Med 58:65-71
Lance, Kevin D; Chatterjee, Anuran; Wu, Bian et al. (2017) Unidirectional and sustained delivery of the proresolving lipid mediator resolvin D1 from a biodegradable thin film device. J Biomed Mater Res A 105:31-41
Fredman, Gabrielle; Hellmann, Jason; Proto, Jonathan D et al. (2016) An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun 7:12859
Colby, Jennifer K; Abdulnour, Raja-Elie E; Sham, Ho Pan et al. (2016) Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia. Am J Pathol 186:1801-1813
Varga, Tamas; Mounier, RĂ©mi; Patsalos, Andreas et al. (2016) Macrophage PPAR?, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration. Immunity 45:1038-1051
Zhang, Michael J; Sansbury, Brian E; Hellmann, Jason et al. (2016) Resolvin D2 Enhances Postischemic Revascularization While Resolving Inflammation. Circulation 134:666-680

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