Obesity threatens the health of children and adults in the U.S. due its strong association with diseases such as metabolic syndrome and Type 2 diabetes. The pro-inflammatory signals induced by obesity are recognized as a mechanism by which obesity causes morbidity and mortality from these diseases. Adipose tissue macrophages (ATMs) are important mediators of obesity-induced inflammation. They are activated in obese fat and dysregulate metabolism by interfering with normal fat cell function. We have made the key discovery that ATMs exist as distinct subtypes that are regulated differently depending on the state of obesity. Recently, studies have demonstrated that T cells also participate in adipose tissue inflammation and may partner with ATMs to cause inflammation in obese adipose tissue. A fundamental unanswered question is: what is the nature of the signals and cell-cell interactions that initiate the inflammatory changes in fat with obesity? This proposal will address this question by examining the hypothesis that ATMs function as antigen presenting cells to communicate with and activate inflammatory CD4+ T cells in fat. This hypothesis is based on our preliminary data demonstrating that ATMs can activate T cells in an antigen-dependent manner. Furthermore, we have identified two receptors found on ATMs that are required to generate the obesity-induced changes in T cells in fat. Our study will apply several technical and conceptual innovations to study the interaction between ATMs and T cells. We propose a model where, in the early stages of obesity, T cells are activated by obesity-induced signals in fat that are transmitted by the resident population of ATMs. With more severe obesity, inflammatory ATMs are recruited to fat and amplify T cell inflammation. We will test this model and reveal the mechanisms behind these events by using mouse models of obesity to address three specific aims. (1) To identify the mechanisms by which obesity alters the ability of ATMs to activate CD4+ T cells. (2) To understand the mechanisms by which MGL1, a receptor found only on resident ATMs, participates in the initiation of adipose tissue inflammation and T cell activation. (3) To assess how antigen presentation on recruited inflammatory ATMs contributes to the maintenance of adipose tissue inflammation. The impact of these inflammatory interactions will be related to the physiologic changes in glucose and lipid metabolism that are relevant to human health. Accomplishing these aims will provide a novel insight into how adipose tissue inflammation is initiated. Importantly, identification of the types of cell-cell communications that regulate inflammation in adipose tissue can identify novel points for intervention to uncouple obesity from its negative effects on health.

Public Health Relevance

Inflammatory activation in obesity contributes to the development of insulin resistance and diabetes. This inflammation is largely generated by the activity of inflammatory cells found in fat tissue that change as fat mass increases. This proposal will investigate how two important inflammatory cells in fat, macrophages and T cells, communicate in adipose tissue. Results of this study could lead to novel therapies for type 2 diabetes that are directed towards blocking obesity-induced inflammation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Abraham, Kristin M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Cho, Kae Won; Zamarron, Brian F; Muir, Lindsey A et al. (2016) Adipose Tissue Dendritic Cells Are Independent Contributors to Obesity-Induced Inflammation and Insulin Resistance. J Immunol 197:3650-3661
Morris, David L; Oatmen, Kelsie E; Mergian, Taleen A et al. (2016) CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity. J Leukoc Biol 99:1107-19
Meyer, Kevin A; Neeley, Christopher K; Baker, Nicki A et al. (2016) Adipocytes promote pancreatic cancer cell proliferation via glutamine transfer. Biochem Biophys Rep 7:144-149
Lumeng, Carey N (2016) Lung Macrophage Diversity and Asthma. Ann Am Thorac Soc 13 Suppl 1:S31-4
Muir, Lindsey A; Neeley, Christopher K; Meyer, Kevin A et al. (2016) Adipose tissue fibrosis, hypertrophy, and hyperplasia: Correlations with diabetes in human obesity. Obesity (Silver Spring) 24:597-605
Reilly, Shannon M; Ahmadian, Maryam; Zamarron, Brian F et al. (2015) A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis. Nat Commun 6:6047
Singer, Kanakadurga; Maley, Nidhi; Mergian, Taleen et al. (2015) Differences in Hematopoietic Stem Cells Contribute to Sexually Dimorphic Inflammatory Responses to High Fat Diet-induced Obesity. J Biol Chem 290:13250-62
Singer, Kanakadurga; Eng, Donna S; Lumeng, Carey N et al. (2014) The relationship between body fat mass percentiles and inflammation in children. Obesity (Silver Spring) 22:1332-6
Cho, Kae Won; Morris, David L; Lumeng, Carey N (2014) Flow cytometry analyses of adipose tissue macrophages. Methods Enzymol 537:297-314
O'Rourke, Robert W; Meyer, Kevin A; Neeley, Christopher K et al. (2014) Systemic NK cell ablation attenuates intra-abdominal adipose tissue macrophage infiltration in murine obesity. Obesity (Silver Spring) 22:2109-14

Showing the most recent 10 out of 31 publications