The problems of obesity and insulin resistance have been linked to type 2 diabetes. Diabetes is on the rise; fully effective treatments are lacking. In the spectrum from obesity, insulin resistance, to diabetes, profound metabolic dysfunction is linked to increased risk for cardiovascular disease. Our goal is to uncover fundamental mechanisms by which macrophage inflammation impacts metabolic dysfunction in high fat feeding and obesity. Our preliminary data reveal that in high fat feeding in mice, ligands of the receptor for AGE (RAGE) are increased in key metabolic tissues even before the development of frank diabetes. Our data reveal that genetic deletion of RAGE results in significant protection against high fat feeding induced obesity and insulin resistance. Importantly, the accumulation, inflammatory polarization, and metabolic properties of adipose tissue macrophages are greatly reduced by deletion of RAGE. We will address the hypothesis that macrophage RAGE regulates obesity, adiposity and metabolic dysfunction in high fat feeding, both inherently and via cross-talk with the adipocyte. Our Project will explore four key properties of macrophage inflammation to discover RAGE-dependent mechanisms in high fat feeding: monocyte recruitment; macrophage retention and stasis; polarization; and metabolic regulation. Finally, we explore how the binding of the RAGE cytoplasmic domain to the formin, mDia1, which is required for RAGE signaling, contributes to macrophage dysfunction in high fat feeding. Translational studies relevant to human subjects will include examination of human adipose tissue macrophages in obesity and, in preclinical models, the testing of novel small molecule antagonists of RAGE signal transduction.

Public Health Relevance

Obesity is a major cause of morbidity and mortality, at least in part through the increased risk for cardiovascular disease. Macrophages play key roles in metabolic dysfunction. Our goal is to understand the mechanisms by which the RAGE signaling pathway in macrophages mediates obesity, insulin resistance, diabetes, and cardiovascular complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK109675-05
Application #
9906204
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Abraham, Kristin M
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Schmidt, Ann Marie (2018) Highlighting Diabetes Mellitus: The Epidemic Continues. Arterioscler Thromb Vasc Biol 38:e1-e8
Lee, Gloria; Plaksin, Joseph; Ramasamy, Ravichandran et al. (2018) Targeted drug discovery and development, from molecular signaling to the global market: an educational program at New York University, 5-year metrics. J Transl Sci 4:1-9
Lee, Gloria; Kranzler, Jay D; Ramasamy, Ravichandran et al. (2018) Training scientists as future industry leaders: teaching translational science from an industry executive's perspective. J Transl Sci 4:
Litwinoff, Evelyn M S; Gold, Merav Y; Singh, Karan et al. (2018) Myeloid ATG16L1 does not affect adipose tissue inflammation or body mass in mice fed high fat diet. Obes Res Clin Pract 12:174-186
Schmidt, Ann Marie (2017) 2016ATVBPlenary Lecture: Receptor for Advanced Glycation Endproducts and Implications for the Pathogenesis an Treatment of Cardiometabolic Disorders: Spotlight on the Macrophage. Arterioscler Thromb Vasc Biol 37:613-621
Shekhtman, Alexander; Ramasamy, Ravichandran; Schmidt, Ann Marie (2017) Glycation & the RAGE axis: targeting signal transduction through DIAPH1. Expert Rev Proteomics 14:147-156