The objective of this proposal is to define the role of innate and adaptive immune mechanisms in the development of insulin resistance and Type II diabetes mellitus (T2DM). T2DM and insulin resistance (IR) are diseases involving inflammation of the adipose and are typified by increases in macrophage (innate) and T cell infiltration of visceral adipose stores and a phenotypic change to a proinflammatory and CD3+ T cell (adaptive) accumulation. The relationship and the relative contributions of these components to T2DM and IR are poorly understood. We have recently observed a dramatic decrease in T regulatory cells (Tregs) in the visceral fat of DIO C57BL/6 mice compared to lean controls with no alteration in splenic populations. Tregs are characterized by the expression of the transcription factor FoxpS, have immunosuppressive functions, can be demonstrated in tissue niches and are protective in chronic inflammatory states, such as atherosclerosis. The long term objective of this project is to show a role for Tregs in the etiology of insulin resistance and the role of innate immune cells in influencing Treg function and differentiation.
Our specific aims are: 1. Investigate the relationship between the development of insulin resistance in diet induced obesity (DIO) in mice and to extend these observations to human adipose samples. 2. Demonstrate that adipose tissue-derived macrophages (CD11b+ cells) and dendritic cells (CD11c+ cells) prevent Treg differentiation in-vitro and to elucidate the mechanism. 3. Determine the impact of systemic Treg depletion on the development of insulin resistance and adipose inflammation. We propose utilizing a unique model that allows us the ability to track and accurately quantify Tregs based upon expression of green fluorescent protein (Foxp3-GFP knockin mice, C57BL/6 background). DIO in these mice will be accomplished by high fat feeding. In-vivo experiments in conjunction with novel in-vitro co-culture experiments that will utilize macrophages and dendritic cells isolated from the adipose of obese and lean wild type mice, co-cultured with splenic CD3+CD4+CD25-GFP- T cells from Foxp3-GFP knockin mice. These experiments will further our understanding of how the innate and adaptive immune systems modulate inflammatory processes in the development of insulin resistance and T2DM in humans. Lay Summary: Insulin resistance and type II diabetes are a burgeoning health crisis in the US and around the world due to increasing rates of obesity. Understanding how the immune system, affected by obesity, promotes these metabolic conditions is central to understanding, preventing, and treating this complex metabolic condition.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F06-E (20))
Program Officer
Castle, Arthur
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Zhong, Jixin; Rao, Xiaoquan; Braunstein, Zachary et al. (2014) T-cell costimulation protects obesity-induced adipose inflammation and insulin resistance. Diabetes 63:1289-302
Deiuliis, Jeffrey A; Oghumu, Steve; Duggineni, Dheeraj et al. (2014) CXCR3 modulates obesity-induced visceral adipose inflammation and systemic insulin resistance. Obesity (Silver Spring) 22:1264-74
Yasmeen, Rumana; Reichert, Barbara; Deiuliis, Jeffrey et al. (2013) Autocrine function of aldehyde dehydrogenase 1 as a determinant of diet- and sex-specific differences in visceral adiposity. Diabetes 62:124-36
Zhong, Jixin; Rao, Xiaoquan; Deiuliis, Jeffrey et al. (2013) A potential role for dendritic cell/macrophage-expressing DPP4 in obesity-induced visceral inflammation. Diabetes 62:149-57
Deiuliis, Jeffrey A; Kampfrath, Thomas; Zhong, Jixin et al. (2012) Pulmonary T cell activation in response to chronic particulate air pollution. Am J Physiol Lung Cell Mol Physiol 302:L399-409
Liu, Cuiqing; Desikan, Rajagopal; Ying, Zhekang et al. (2012) Effects of a novel pharmacologic inhibitor of myeloperoxidase in a mouse atherosclerosis model. PLoS One 7:e50767
Deiuliis, J A; Kampfrath, T; Ying, Z et al. (2011) Lipoic acid attenuates innate immune infiltration and activation in the visceral adipose tissue of obese insulin resistant mice. Lipids 46:1021-32
Shah, Zubair; Pineda, Colleen; Kampfrath, Thomas et al. (2011) Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways. Vascul Pharmacol 55:2-9
Deiuliis, Jeffrey; Shah, Zubair; Shah, Nilay et al. (2011) Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PLoS One 6:e16376
Deiuliis, Jeffrey A; Liu, Li-Fen; Belury, Martha A et al. (2010) Beta(3)-adrenergic signaling acutely down regulates adipose triglyceride lipase in brown adipocytes. Lipids 45:479-89