HL-142: Obesity and its accompanying metabolic disorders represent the great public health challenge of our time and is considered an independent risk factor for cardiovascular disease (CVD). Adipose tissue (AT) expansion and remodeling is an ongoing process that is pathologically altered in the obese state, which is characterized by increased pro-inflammatory state, inadequate angiogenic response and fibrosis. Although adipocytes are key players orchestrating local changes in the microenvironment, much evidence also points towards a pivotal role for macrophages in such remodeling events, by affecting both adipocyte and endothelial cell (EC) angiogenic functions. Because angiogenesis is a rate-limiting step for AT remodeling, it is essential to understand the crosstalk between macrophages and ECs. It is accepted that obesity is accompanied by a change in the composition of macrophages, from an anti-inflammatory and angiogenic form, to a highly inflammatory form responsible for the negative outcomes that arise from obesity. Important players of the post-transcriptional regulatory network are the small non- coding RNAs, microRNAs (miRNAs), which have a demonstrated role in the control of transcriptional networks in M?s. Intriguingly, miRNAs can be transferred from cell to cell by exosomes, thus facilitating the exchange of information among cells. The molecular composition and content of exosomes may vary depending on whether the secretion is constitutive or a consequence of cell activation. We hypothesize that in obese AT, activated macrophages produce exosomes that contain a specific set of miRNAs that target ECs modulating their function, by controlling gene expression and therefore affecting AT expansion and remodeling. This project will: answer important questions regarding exosome specificity and function; provide critical insights into the contribution of macrophage-derived microRNAs as vehicles of paracrine communication between macrophage and ECs in the regulation angiogenesis in the AT. These findings will pave the way to the identification of innovative therapeutic strategies to modulate AT expansion and remodeling during obesity.

Public Health Relevance

The proposal main goal is to investigate the contribution of microRNAs secreted by macropage in the regulation angiogenesis in the obese adipose tissue. This work will provide critical insight into fundamental regulatory mechanisms and will pave the way to the identification of innovative therapeutic strategies to modulate adipose tissue expansion and remodeling during obesity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL135012-01A1
Application #
9380787
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Olive, Michelle
Project Start
2017-06-15
Project End
2021-02-28
Budget Start
2017-06-15
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
$526,339
Indirect Cost
$212,107
Name
Yale University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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