Alastair Kerr

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. 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. 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 identify disease-regulated lncRNAs and test how they function in human adipocytes. I will use gene editing techniques and lipid/metabolomics analysis to define the role of these lncRNAs in lipid storage and FA release. 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. 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.

Energy is stored in the form of triglyceride ready for breakdown into fatty acids (FAs) and release into the circulation. In obesity, the adipose tissue dysfunctions, resulting in high spontaneous release and low capacity for further FAs mobilization in states of demand. Chronic release and elevation of systemic FAs is a major driver of type-2 diabetes pathogenesis.My research will understand how long non-coding RNAs (lncRNAs) function throughout the adipocyte to control lipid storage and contribute to the dysregulated FAs release in obesity. I have developed methodology to study lncRNAs in human fat cells including a novel beyond-state-of-the-art technique to identify the specific interacting proteins, termed TROOPS.I will use unique and extensive clinical white adipose tissue biopsy data to identify disease regulated lncRNAs. I will map how these lncRNAs function in human adipocytes using cutting-edge gene editing techniques and lipid/metabolomics. Coupling protein-lncRNA complex purification with electron microscopy, I will understand how lncRNAs function at a molecular resolution. Finally, using large population genomics and genetic variant base-editing in patient derived adipocytes, I will identify causal variants in lncRNA loci driving cardiometabolic disease. The results will provide a shift in understanding for how lncRNAs enable the adipocyte to perform specialized lipid handling functions and how alterations in these lncRNAs leads to maladaptation.