A Novel Paradigm of Intracrine Fatty Acid Receptor Signalling at Lipid Droplets: Implications for Adipocyte Physiology and Metabolic Disease

Obesity is a growing global health concern, affecting more than 650 million people worldwide and predicted to cost over US$1 trillion by 2025. The adipose tissue serves as an important storage of energy in the form of fatty acids contained in fat. Inside adipose cells, fatty acids are stored in specialized cellular structures known as 'lipid droplets', from where they are released during fasting in a process termed lipolysis. When someone develops obesity, their body stores an excessive amount of fat, leading to health problems. One major issue is that fat accumulation significantly increases the risk of cardiovascular diseases such as heart attacks and strokes. Additionally, it can lead to insulin resistance, causing diabetes, and inflammation, affecting the function of several organs such as the liver. This project addresses the urgent need to better understand the fundamental cellular and molecular mechanisms that control the storage and release of fatty acids in order to develop improved therapies for obesity-related metabolic disorders. G-protein-coupled receptors (GPCRs), the largest family of receptors in the human body and ideal drug targets, are well known to play important roles in the control of fatty acid storage and release. However, progress in the field has been hampered by the long-held belief that these receptors were only active at the cell surface, and, therefore, could not sense the intracellular concentration of metabolites such as fatty acids. While this dogma has been challenged by us and other with the demonstration that GPCRs can also function inside cells, the relevance of these emerging ideas for metabolite-sensing GPCRs remains to be explored. Free fatty acid receptors 2 and 4 (FFA2/4), two GPCRs activated by fatty acids in adipose cells, are under consideration as potential drug targets for obesity-related metabolic disorders. Exciting preliminary results by our team indicate that FFA2/4 might have to be precisely located and function inside cells in close proximity to lipid droplets to efficiently sense the released fatty acids and inhibit lipolysis. However, the underlying mechanisms, physiological relevance and implications for drug therapy of this novel potential modality of 'intracrine' FFA2/4 signalling are presently unknown. In this application, we will combine state-of-the-art cell signalling, pharmacology and advanced imaging techniques with innovative cell and mouse models as well as tissue samples from patients with obesity to elucidate the cellular and molecular mechanisms of 'intracrine' FFA2/4 signalling, its relevance to human physiology and disease, and implications for drug therapy. Our research holds promise for identifying novel molecular mechanisms involved in the control of fatty acid storage and release in physiology and disease, with potential implications for the therapy of obesity-related metabolic disorders.