How Beige Fat Works to Promote Healthy Blood Pressure in Mice

Studies in mice suggest that beige fat surrounding blood vessels actively works to keep high blood pressure in check, promoting healthy vascular function even during obesity. Building on clinical evidence that people with brown fat have lower odds of hypertension, the researchers, headed by a team at The Rockefeller University, created mouse models genetically engineered to lack functional thermogenic beige fat tissue, a type of adipose tissue that is distinct from white fat and that helps the body burn energy. In mice, beige fat is the thermogenic fat depot that most closely resembles adult human brown fat.

The scientists found that in these animals, loss of beige fat increased blood vessel sensitivity to one of the most important vasoconstricting hormones (angiotensin II), and that blocking an enzyme, QSOX1, involved in stiffening vessels and disrupting normal signaling, can restore healthy vascular function in mice.

The results 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,” said Paul Cohen, MD, PhD, 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.”

Senior author Cohen, together with first author Mascha Koenen, PhD, and colleagues reported on their findings in Science, in a paper titled “Ablation of Prdm16 and beige fat identity causes vascular remodeling and elevated blood pressure.”

Obesity causes hypertension. Hypertension causes cardiovascular disease. And cardiovascular disease is the leading cause of death worldwide. “Excess adiposity is a major risk factor for hypertension and heart disease,” the authors wrote. “Hypertension is a major risk factor for coronary heart disease and stroke, and even mild, chronically increased blood pressure is associated with end-organ damage and increased mortality.”

While the link between fat and high blood pressure is clearly central to this deadly chain, its biological basis long remained unclear. “The type of adipose tissue more than the total amount is a particularly critical factor in blood pressure regulation,” the authors continued.

Cohen and colleagues were 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 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. “Whereas excess white fat, especially visceral adiposity, is associated with elevated blood pressure, brown fat is associated with reduced odds of hypertension, even in obesity,” they wrote.

However, 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,” said Mascha Koenen, PhD, a postdoctoral fellow in the Cohen lab.

For their newly reported study the team engineered mouse models that were healthy in every way except for a complete loss of beige fat identity, the murine counterpart of inducible brown fat seen in adult humans. By deleting the Prdm16 gene—a major gene expression regulator of the adipose beiging process—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. “Adipocyte-specific ablation [or conditional knockout (cKO)] of Prdm16 (PRDM16^cKO) leads to the loss of beige fat identity, providing a genetic tool to study the effect of this tissue on vascular function,” they noted.

“We didn’t want the model to be analogous to an obese versus lean individual,” Koenen explained. “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.”

The effects in mice lacking beige fat were evident. The perivascular adipose tissue (PVAT) 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 also exhibited 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 commented.

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, QSOX1, secreted by these adipocytes, 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. “We show that the circulating enzyme QSOX1 is derepressed in Prdm16-deficient adipocytes, and deletion of Qsox1 in Prdm16 conditional knockout mice prevented vascular fibrosis and normalized vascular reactivity,” they reported. “Taken together, simultaneous loss of Prdm16 and Qsox1 in adipocytes prevented vascular fibrosis and ANGII-mediated hypercontractility observed in PRDM16^cKO mice.”

The collective 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. “Individuals lacking active brown fat have higher odds of hypertension, which suggests a protective role for thermogenic fat,” they noted. “Moreover, we found that humans lacking detectable brown fat showed clinical sequelae of long-term blood pressure elevation.”

The study is a demonstration of “reverse translation,” which is often employed by physician-scientists. 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 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.

“This study highlights the importance of adipocyte identity and the potential of targeting QSOX1 to prevent or treat vascular fibrosis and hypertension while establishing a causal link between beige adipocytes and cardiovascular health,” the team concluded.

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 said.

In a related perspective, Mandy O. J. Grootaert, PhD, and Aernout Luttun, PhD, at the department of cardiovascular sciences KU Leuven, commented, “Koenen et al.’s findings suggest that the activation of brown adipose tissue by boosting or stabilizing PRDM16 expression could have cardiovascular benefits. Although current human and nonhuman data are encouraging, well-controlled clinical trials are needed to determine whether triggering beiging of adipose tissue reduces the frequency of adverse cardiovascular events in patients.”