Recent work suggests a prominent role for adipose inflammation in diet induced obesity (DIO) and its metabolic and cardiovascular complications. For example, CCR2, a chemokine receptor, has been implicated in inflammatory monocyte recruitment into obese adipose and into neointima of atherosclerosis. Fractalkine (CX3CL1) and its monogamous receptor (CX3CR1) are also atherogenic and emerging data show additive roles for CX3CL1-CX3CR1 and CCR2 in atherosclerosis. In preliminary studies, we demonstrate that CX3CL1 is markedly induced in adipose inflammation, adipose CX3CL1 is increased in human and rodent obesity, fatty acids and adipocytokines induce CX3CL1 in adipocytes, monocytes adhere to human adipocytes in a CX3CR1-dependent manner, and CX3CR1 deficiency modulates adipose function and energy homeostasis in high-fat fed mice. Thus, CX3CL1-CX3CR1 appears to be one of very few chemokine pathways implicated in both obesity and atherosclerosis and therefore is the focus of this proposal. Further, unlike other chemokines e.g., CCR2, CX3CL1-CX3CR1 may be a relatively safe therapeutic target in human. We propose that CX3CL1 recruits circulating monocytes, independent of CCR2, driving adipose tissue macrophage (ATM) accumulation and survival, leading to insulin resistance and obesity on high-fat diet. The goal of this proposal, using mice models and human translation, is to determine whether fractalkine (CX3CL1-CX3CR1) modulates adipose inflammation and its metabolic consequences and if this action is independent of CCR2.
Aim 1 will characterize effects of CX3CL1 deficiency and disruption of CX3CR1 signaling on diet-induced adipose inflammation, energy and glucose homeostasis, and obesity in mice.
Aim 2 will determine how CX3CL1 interacts with CCR2 in diet-induced adipose inflammation, insulin resistance and obesity in mice.
Aim 3 will address the hypothesis that functional variation in CX3CR1 will affect adipose inflammation and insulin resistance in humans. We will also utilize adipocytes, derived from mouse embryonic fibroblast, and primary human adipocytes to study the role of CX3CL1 in adipocyte induction of monocyte recruitment, adhesion, activation and survival. These studies will define causality and mechanism while providing the human context for clinical and therapeutic development of CX3CL1-CX3CR1 in DIO and its complications.

Public Health Relevance

Adipose inflammation contributes to metabolic complications including diabetes and heart disease in obesity. We hypothesize that fractalkine, which can recruit inflammatory cells to tissues, promotes adipose inflammation and metabolic complications on high-fat diets and obesity. We will test whether deletion of fractalkine signaling in mice or genetic variation in humans blocks adipose inflammation and its metabolic complications. This work may lead to novel therapeutics that block fractalkine action and thus reduce complications of obesity including diabetes and heart disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Abraham, Kristin M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Ferguson, Jane F; Mulvey, Claire K; Patel, Parth N et al. (2014) Omega-3 PUFA supplementation and the response to evoked endotoxemia in healthy volunteers. Mol Nutr Food Res 58:601-13
McGillicuddy, Fiona C; Moll, Herwig P; Farouk, Samira et al. (2014) Translational studies of A20 in atherosclerosis and cardiovascular disease. Adv Exp Med Biol 809:83-101
O'Neill, S M; Hinkle, C; Chen, S-J et al. (2014) Targeting adipose tissue via systemic gene therapy. Gene Ther 21:653-61
Liu, Yichuan; Ferguson, Jane F; Xue, Chenyi et al. (2014) Tissue-specific RNA-Seq in human evoked inflammation identifies blood and adipose LincRNA signatures of cardiometabolic diseases. Arterioscler Thromb Vasc Biol 34:902-12
Ferguson, J F; Ryan, M F; Gibney, E R et al. (2014) Dietary isoflavone intake is associated with evoked responses to inflammatory cardiometabolic stimuli and improved glucose homeostasis in healthy volunteers. Nutr Metab Cardiovasc Dis 24:996-1003
Zhang, Hanrui; Reilly, Muredach P (2014) Anti-inflammatory effects of high-density lipoprotein through activating transcription factor 3: benefit beyond cholesterol transport-dependent processes. Arterioscler Thromb Vasc Biol 34:e11-2
Wojczynski, Mary K; Li, Mingyao; Bielak, Lawrence F et al. (2013) Genetics of coronary artery calcification among African Americans, a meta-analysis. BMC Med Genet 14:75
Foulkes, Andrea S; Matthews, Gregory J; Das, Ujjwal et al. (2013) Mixed modeling of meta-analysis P-values (MixMAP) suggests multiple novel gene loci for low density lipoprotein cholesterol. PLoS One 8:e54812
Ferguson, Jane F; Patel, Parth N; Shah, Rhia Y et al. (2013) Race and gender variation in response to evoked inflammation. J Transl Med 11:63
Liu, Yichuan; Ferguson, Jane F; Xue, Chenyi et al. (2013) Evaluating the impact of sequencing depth on transcriptome profiling in human adipose. PLoS One 8:e66883

Showing the most recent 10 out of 11 publications