How beige fat keeps blood pressure in check

Obesity causes hypertension. Hypertension causes cardiovascular disease. And cardiovascular disease is the leading cause of death worldwide. While the link between fat and high blood pressure is clearly central to this deadly chain, its biological basis long remained unclear. What is it about fat that impacts vascular function and blood pressure control?

Now, a new study demonstrates how thermogenic beige fat—a type of adipose tissue, distinct from white fat, that helps the body burn energy—directly shapes blood pressure control. Building on clinical evidence that people with brown fat have lower odds of hypertension, the researchers created mouse models that cannot form beige fat (the thermogenic fat depot in mice that most closely resembles adult human brown fat) to watch what happens when this tissue is lost. They found that the loss of beige fat increases the sensitivity of blood vessels to one of the most important vasoconstricting hormones (angiotensin II)—and that blocking an enzyme involved in stiffening vessels and disrupting normal signaling can restore healthy vascular function in mice. These results, published in Science, reveal a previously unknown mechanism driving high blood pressure and point toward more precise therapies that target communication between fat and blood vessels.

"We've known for a really long time that obesity raises the risk of hypertension and cardiovascular disease, but the underlying biology has never been fully understood," says Paul Cohen, head of the Weslie R. and William H. Janeway Laboratory of Molecular Metabolism. "We now know that it's not just fat, per se, but the type of fat—in this case, beige fat—that influences how the vasculature functions and regulates the whole body's blood pressure."

All fat is not the same

Cohen and colleagues were well aware that brown fat held clues to the mystery of hypertension. Found in newborns, animals, and some adults (typically around the neck and shoulders) brown fat burns energy and generates heat, unlike its better known cousin, white fat, which stores calories. Prior work from the lab had shown that individuals with more brown fat have significantly lower odds of hypertension and other cardiometabolic disorders. But this patient data could only establish correlation. Demonstrating causation—and uncovering the mechanism at play—would require controlled experiments in the lab.

"We knew there was a link between thermogenic adipose tissue—brown fat—and hypertension, but we had no mechanistic understanding of why," says Mascha Koenen, a postdoctoral fellow in the Cohen lab.

So the team engineered mouse models that were healthy in every way except for one: a complete loss of beige fat identity, the murine counterpart of inducible brown fat seen in adult humans. By deleting the Prdm16 gene specifically in fat cells, the researchers selectively removed beige fat identity in otherwise healthy mice, isolating the beige fat variable from confounding factors, such as obesity or inflammation. "We didn't want the model to be analogous to an obese versus lean individual," Koenen explains. "We wanted the only difference to be whether the fat cells in the mouse were white or beige. In that way, the engineered mice represent a healthy individual who just happens to not have brown fat."

It was a seemingly minor change with outsize impact. The fat that wraps around the blood vessels of these engineered mice began expressing the markers of white fat, including angiotensinogen, a precursor to a major hormone that increases blood pressure. The mice had elevated blood pressure and mean arterial pressure, and tissue analysis revealed that stiff, fibrous tissue had begun to accumulate around the vessels. And when the team tested arteries from these animals, they found that the vessels had developed a striking hypersensitivity to angiotensin II, one of the body’s strongest blood pressure signals.

"We were surprised to find such drastic remodeling of adipose tissue lining the vasculature," Koenen says.

Further, single-nucleus RNA sequencing revealed that, absent beige fat, vascular cells had switched on a gene program that promotes stiff, fibrous tissue, which makes blood vessels less flexible, forces the heart to pump harder, and raises blood pressure. To pinpoint the signal responsible for these changes, the team tested secreted mediators released by fat cells deficient in beige fat, and found that transfer of this fluid onto vascular cells alone could activate the genes that promote fibrous tissue.

With the help of large gene and protein expression datasets, the researchers identified a single enzyme secreted by these adipocytes, QSOX1, which has been tied to tissue remodeling in cancer. They discovered that beige fat normally keeps QSOX1 turned off but, when beige identity is lost, the enzyme is overproduced and this kicks off a cascade of events that lead to hypertension. Finally, to confirm that QSOX1 was the culprit, the team engineered mice with neither Prdm16 nor Qsox1. These mice, as predicted, did not have beige fat or vascular dysfunction.

Together, the data reveal an obesity-independent signaling axis in which the loss of beige fat identity unleashes QSOX1, triggering harmful remodeling of blood vessels and raising blood pressure. The researchers also report that, in large clinical cohorts, people carrying mutations in PRDM16—the same gene whose loss activates QSOX1 in mice—show higher blood pressure, indicating that their observations of beige fat and hypertension in mice translate well to humans.

The enzyme that raises blood pressure

The study is a victory for a scientific methodology known as “reverse translation,” often employed by physician-scientists like Cohen. In this case, Cohen, who treats patients at Memorial Sloan Kettering, used mouse models in the lab to explain a puzzling phenomenon manifesting in his human patients. This iterative cycle between human biology and mechanistic experimentation uncovered a new molecular entry point for understanding, and potentially treating, hypertension.

The findings here advance the Cohen lab's overarching mission to uncover the cellular and molecular mechanisms by which obesity drives downstream disease, offering a new mechanistic explanation for an obesity-associated condition. These results could open broad avenues for future work, from examining how QSOX1 reshapes the scaffolding around blood vessels and pinpointing which parts of the angiotensin receptor it may alter, to exploring how differences in fat surrounding the vasculature influences where disease is most likely to develop.

The results also raise the possibility of future therapeutic approaches for hypertension, including the prospect of targeting QSOX1. "The more we know about these molecular links, the more we can move towards conceiving of a world where we can recommend targeted therapies based on an individual’s medical and molecular characteristics,” Cohen says.