Glycerolipid Cycling in Thermogenesis, Energy Homeostasis, Signaling, and Diseases

Mammals maintain body heat by adaptive energy expenditure through different organ-specific mechanisms. The glycerolipid/free fatty acid (FFA) cycle (glycerolipid cycle), encompassing triglyceride lipolysis and FFA release followed by their reesterification, is an ATP-consuming process that contributes to energy expenditure, heat production, and various lipid signaling pathways. The glycerolipid cycle, which was originally described as a whole body process, is now known to also occur intracellularly in many organs. This review focuses on the thermogenic and signaling roles of glycerolipid cycling in adipose and other tissues and offers insight into the various pathophysiological conditions where its activity is altered. We discuss its substrates and products, enzyme components, and regulation. We present evidence that this cycling process, besides acting as the complete triglyceride/FFA cycle, is in fact composed of multiple shorter subcycles, which can be activated individually. We highlight the importance of this energy-dissipating cycle in adaptive thermogenesis and energy expenditure in animals and humans and discuss the latest methodological advances to quantify its flux. The much renewed interest in this area has begun to showcase the central role of glycerolipid cycling mediated thermogenesis and signaling in cardiometabolic diseases, cancer, and aging that could be harnessed for therapy.