Energetic Stress-Induced Metabolic Regulation by Extracellular Vesicles

Abstract

Recent studies have demonstrated that extracellular vesicles (EVs) serve powerful and complex functions in metabolic regulation and metabolic-associated disease, although this field of research is still in its infancy. EVs are released into the extracellular space from all cells and carry a wide range of cargo including miRNAs, mRNA, DNA, proteins, and metabolites that have robust signaling effects in receiving cells. EV production is stimulated by all major stress pathways and, as such, has a role in both restoring homeostasis during stress and perpetuating disease. In metabolic regulation, the dominant stress signal is a lack of energy due to either nutrient deficits or damaged mitochondria from nutrient excess. This stress signal is termed "energetic stress," which triggers a robust and evolutionarily conserved response that engages major cellular stress pathways, the ER unfolded protein response, the hypoxia response, the antioxidant response, and autophagy. This article proposes the model that energetic stress is the dominant stimulator of EV release with a focus on metabolically important cells such as hepatocytes, adipocytes, myocytes, and pancreatic β-cells. Furthermore, this article will discuss how the cargo in stress-stimulated EVs regulates metabolism in receiving cells in both beneficial and detrimental ways. © 2023 American Physiological Society. Compr Physiol 13:5051-5068, 2023.

Figure 1.

Convergent energetic stress responses of obesity, starvation, and exercise. A. Energetic stress induced by obesity, starvation and exercise results in low amino acid levels, low energy charge, high NAD⁺ levels, high ROS and increased circulating lipids. Each of these stress signals activates the respective sensor enzyme as indicated or amplifies other stress signals. B. The stress signals and sensor pathways activate highly interconnected stress response pathways: antioxidant, hypoxia, ER UPR and autophagy. These pathways are known regulators of EV release, however, how they interact to accomplish this is not understood. C. The convergent regulation of the endolysosomal system by stress pathways may account for the net increase in EV release during energetic stress.

Figure 2.

Categories describing the effect of energetic stress-induced EVs on receiving cells. A. Cells that are sensitive to a specific stress, such as adipocytes, can send out warning signals via EVs that enhance the resilience of the receiving cell. B. Stressed cells can also release EVs contain damage and pathology-spreading molecules. C. EVs from support cells, particularly stem cells, can produce EVs that contain inherently protective molecules such as antioxidant enzymes. These EVs protect organs such as the kidney, brain, and liver from oxidative stress and aging. D. EVs from stressed cells have a capacity to recruit needed resources from other cells. This is exemplified by cancer cells or myocytes using EVs to request fatty acids from adipocytes as a source of energy. In addition, these EVs signal to attract immune cells, in the case of obese adipose tissue, and endothelial cells, in the case of a tumor, obese adipose tissue and exercising muscle.