Understanding how long non-coding RNAs adapt the adipocyte for specialised lipid storage and breakdown.

Introduction

Energy is stored in adipocytes as a large uniocular lipid droplet, which can be broken down into fatty acids (FAs) and released into the circulation when needed. This specialised lipid storage and breakdown requires dynamic organisation of metabolic enzymes and cofactors around the large lipid droplet for metabolic homeostasis. In obesity, the adipocyte dysfunctions, resulting in high spontaneous release of FAs. This chronic release and elevation of systemic FAs is a major driver of systemic insulin resistance, type 2 diabetes, and other cardiometabolic diseases.

Research Hypothesis

I postulate that long non-coding RNAs (lncRNAs) interact with the metabolic machinery within the adipocyte to organize cell- and stimulation-specific interactomes, channelling substrate flux within the cell. Adipocytes express over 4000 lncRNAs, many of which are unique to humans and this cell type. However, whether these lncRNAs contribute to the adipocyte’s specialised lipid metabolism in health and disease is not understood. This proposed research aims to address this question.

Methodologies

I have already developed key methodologies to study lncRNAs in human adipocytes, including a novel technique called TROOPS that identifies specific lncRNA-interacting proteins. Leveraging an extensive bank of white adipose tissue biopsies from uniquely characterized patients, I will:

1. Identify disease-regulated lncRNAs.
2. Test how they function in human adipocytes.
3. Use gene editing techniques and lipid/metabolomics analysis to define the role of these lncRNAs in lipid storage and FA release.

Advanced Techniques

Furthermore, I will use protein-lncRNA complex purification combined with advanced microscopy techniques to reveal how lncRNAs can sequester protein complexes into phase-separated organelles and organize adipocyte lipid metabolism.

Expected Outcomes

These insights will provide a paradigm shift in understanding how lncRNAs enable the adipocyte to perform specialized functions and new generalizable findings for how lncRNAs contribute to cell function.