Insulin is a key metabolic hormone and growth factor best known for its role in glucose homeostasis. Because responses to insulin are frequently dysregulated in metabolic disease, the relevant signaling pathways in parenchymal cells of metabolic tissues (adipocytes, skeletal myocytes, and hepatocytes) have been extensively characterized. In contrast, insulin signaling in other cell types, such as tissue resident macrophages, is much less clear. However, given the pivotal role of resident macrophages in tissue function and physiology, as well as in the pathogenesis of metabolic disease, it is important to understand how insulin affects their behavior and function. In this project we plan to explore how insulin, a reliable indicator of food intake, signals to macrophages and affects their polarization according to different needs in the fed or fasted state. Preliminary experiments suggest insulin signaling in macrophages is different from that in metabolic tissues. Most strikingly, there is an apparent lack of downstream signaling upon in vitro stimulation of macrophages with physiological concentrations of insulin, despite robust expression of the receptor. In the first aim, we plan to study the mechanistic basis of this observation, and how changes in signaling architectures may sensitize macrophages to insulin signaling, which we have observed. The role of insulin signaling in macrophages has been studied in the context of various disease processes. However, a clear logic to the effects of insulin signaling remains elusive. Furthermore, many studies are confounded by the use of supraphysiological concentrations of insulin, which may cause cross reactivity with other receptors such as the insulin-like growth factor 1 receptor, also expressed by macrophages, or other nonspecific surface receptors. Some preliminary data suggest insulin may have an effect on macrophage alternative activation in response to interleukin 4. To further define the role of insulin signaling in macrophages in relation to tissue function, in the second aim I plan to assess how insulin may affect M2 polarization and wound healing.

Public Health Relevance

At least one third of the national population is affected by obesity and metabolic syndrome, characterized by dysregulated insulin signaling and increased risk for diabetes, heart disease, and cancer. While insulin signaling in metabolic tissues has been thoroughly investigated, a clear picture of insulin signaling to tissue resident macrophages, which play key roles in physiology and disease, is lacking. Studying this will improve our understanding of how macrophages sense and incorporate endocrine signals into their behavior, and may uncover new therapeutic and diagnostic targets for metabolic disease and associated comorbidities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30DK113731-01A1
Application #
9467946
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Castle, Arthur
Project Start
2017-09-01
Project End
2020-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Graduate Schools
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520