Your blood carries more than oxygen. It's also running a communication system most people don't know exists.
Cells throughout the body communicate constantly, not only through nerves and hormones but also through microscopic particles circulating in the blood. Among the most important of these are small extracellular vesicles. These are tiny, membrane-bound spheres released by cells into bodily fluids(1).
Though invisible to the naked eye, they are extraordinarily abundant with billions being found in a single milliliter of blood. These vesicles act as mobile carriers, transporting
proteins, fats, and genetic material from one cell to another(2).
Over the past decade, researchers have come to recognize small extracellular vesicles as an essential communication system that helps coordinate immune responses, metabolism, and organ function.
One molecule of particular interest is proopiomelanocortin (POMC). POMC is not an active hormone itself. Instead, it is a precursor protein that can be cut into several biologically powerful hormones, including(3):
For decades, scientists have known that uncut, full-length POMC circulates in the bloodstream at much higher levels than its processed hormones. What puzzled researchers was why this inactive-looking molecule was present at all and what purpose it served outside hormone-producing glands.
Recent research has uncovered an unexpected answer. A portion of circulating POMC is physically attached to small extracellular vesicles.
Even more striking, during
intense physical exercise, the amount of POMC bound to these vesicles increases by roughly fourfold despite no meaningful change in total POMC levels or the number of vesicles in the blood(4).
This suggests that exercise does not increase hormone production so much as it changes how hormones are handled and transported.
Intense exercise causes a mild, temporary drop in blood pH and is a normal consequence of increased metabolic activity. While subtle, this shift turns out to matter.
Changes in acidity can alter the three-dimensional shape of proteins. In this case, the altered environment allows POMC to bind more readily to specific receptors embedded in the membranes of small extracellular vesicles.
Once bound, POMC becomes part of a vesicle-bound complex rather than floating freely in the bloodstream.
Rather than thinking of this as a chemical trick, it may be more accurate to see it as conditional compatibility, under exercise-induced stress, POMC adopts a structure that makes vesicle binding possible.
Figure: Results suggest that the temporary blood acidification induced by vigorous exercise increases affinity between MC-Rs, particularly MC1-R, and POMC Adapted from M. F. Santos, J. Randa, D. Tai, G. Vistoli, N. A. Schahaf, S. Vittorio, et al.(4)
One of the most important consequences of this shift involves the blood–brain barrier, which is a tightly regulated boundary that protects the brain by limiting what substances can enter.
Free-floating POMC crosses this barrier inefficiently. When attached to small extracellular vesicles; POMC is transported across far more effectively. Vesicles appear to provide a protected, receptor-guided route that allows hormone signals to reach brain tissue under conditions of physical stress(4).
This may help explain how exercise rapidly influences brain-related functions such as pain perception, stress resilience, mood, and energy regulation.
Importantly, POMC does not become biologically inactive when bound to vesicles. Experiments show that vesicle-associated POMC can still trigger meaningful cellular responses, including stimulating pigment production in skin cells, which is a well-established POMC-related effect.
In other words, vesicle binding does not neutralize POMC. It preserves its signaling capacity while extending its reach.
This work offers a plausible explanation for a long-standing mystery, which is why large amounts of unprocessed POMC circulate in the blood at all.
Rather than being a passive byproduct, POMC may function as a circulating reserve, capable of being mobilized under physical stress. Exercise appears to shift POMC into a form that is better protected, more mobile, and more likely to reach sensitive targets such as the brain and immune system.
Beyond exercise physiology, these findings have implications for medicine and drug development. Many therapies target the same receptors involved in POMC signaling, including opioid and melanocortin receptors.
Understanding how vesicles influence hormone availability and transport may improve predictions about drug distribution and effectiveness.
But more broadly, the study highlights a previously underappreciated principle: hormones do not act alone. Their biological impact may depend as much on how they are packaged and transported as on how much of them is produced.
This emerging view reframes exercise not only as a stimulus for hormone release, but as a system-wide organizer of hormone delivery, fine-tuning where and how signals act when the body is under stress.
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References:
1. Mathieu M, Martin-Jaular L, Lavieu G, et al: Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol 21:9-17, 2019
2. Salomon C, Das S, Erdbrügger U, et al: Extracellular Vesicles and Their Emerging Roles as Cellular Messengers in Endocrinology: An Endocrine Society Scientific Statement. Endocr Rev 43:441-468, 2022
3. Harno E, Gali Ramamoorthy T, Coll AP, et al: POMC: The Physiological Power of Hormone Processing. Physiol Rev 98:2381-2430, 2018
4. Santos MF, Randa J, Tai D, et al: Physical exercise increases binding of POMC to blood extracellular vesicles. Proc Natl Acad Sci U S A 122:e2525044122, 2025
