Kristine Kyle de Leon - PhD Scholarship 2023

Project summary:
The role of microRNAs in the obese adipose vascular niche

Obesity is intimately linked to comorbidities like type 2 diabetes and cardiovascular disease, and disease progression is tightly associated with metabolic abnormalities in adipocytes (AC) and endothelial cells (adEC) within the adipose tissue microenvironment. This project aims to uncover whether extracellular vesicles bearing small, regulatory RNAs termed ‘microRNAs ’(miRNAs) govern AC-adEC crosstalk in the obese adipose tissue, thereby contributing to vascular dysfunction. Through use of advanced computational analyses and a novel transgenic mouse model, we seek to unveil cellular-level miRNAs exchanges within the adipose tissue. In summary, our goal is to shed light on the progression of cell-intrinsic AC and adEC dysfunction and metabolic disease development, as well as the contribution of miRNA paracrine crosstalk during this process.

Project Title

The role of microRNAs in the obese adipose vascular niche

Background

Obesity is a major contributor to the development and deterioration of complex metabolic diseases, such as type 2 diabetes and cardiovascular disease. It also influences the development of cell-intrinsic dysfunction within adipocytes (AC) and endothelial cells of the adipose (adEC), thus affecting AC-adEC cellular interplay and intercellular communication. MicroRNAs (miRNAs) are important post-transcriptional gene regulators within cells but, importantly, can also be exchanged between cells within adipose tissue by means of extracellular vesicles (‘exosomes’). However, miRNAs controlling paracrine crosstalk between adipocytes and endothelial cells of the adipose tissue, and the relevance of this extracellular vesicle transfer for development of endothelial vascular dysfunction and cardiovascular disease, has not been addressed to date.

Aim

Our research aims to provide evidence of the extracellular vesicle-mediated exchange of key miRNAs between AC and adEC within the obese adipose tissue. Additionally, we aim to investigate the functional significance of these miRNAs in cellular metabolic homeostasis using in vitro/in vivo miRNA gain- and loss-of-function approaches.

Methods

In this project, we will characterize obesity-induced miRNA changes within adipocytes and adipose endothelial cells through miRNA bulk RNA-Sequencing. This will be followed by advanced data analyses that integrate existing miRNA single-cell RNA-Seq data to infer miRNA activities and identify miRNAs involved in AC-adEC paracrine communication in intact adipose biopsies from human and mice. Using a novel transgenic mouse line (ExoRep), we will trace extracellular vesicle-mediated miRNA exchange between AC and adEC in a cell-intrinsic manner and study miRNA release and extracellular vesicle trafficking between donor and recipient cells.

Preliminary results

Preliminary data from Prof. Kornfeld’s group suggest that repression of fatty acid biosynthesis is a critical regulatory event during the onset of diet-induced obesity in adipocytes, and that this process is strongly dependent on miRNA regulation, highlighting their significance for obesity-related cellular dysfunction.

Additional information

I will be affiliated with the Novo Nordisk Foundation Center for Adipocyte Signaling (ADIPOSIGN), where my main supervisor, Jan-Wilhelm Kornfeld, is one of the founding PIs.