Obesity is a major risk factor for hypertension, which in turn leads to cardiovascular disease, the leading cause of death worldwide. The biological mechanisms connecting fat tissue and high blood pressure have remained unclear.
A new study published in Science has identified how thermogenic beige fat—a type of fat that helps burn energy—affects blood pressure regulation. Researchers used mouse models unable to form beige fat, closely resembling adult human brown fat, to observe the effects of its absence. They found that losing beige fat made blood vessels more sensitive to angiotensin II, a hormone that constricts blood vessels and raises blood pressure. Blocking an enzyme involved in vessel stiffening restored normal vascular function in these mice.
Mascha Koenen, a postdoctoral fellow involved in the research, stated: "We knew there was a link between thermogenic adipose tissue-brown fat-and hypertension, but we had no mechanistic understanding of why."
The team engineered mice lacking the Prdm16 gene specifically in their fat cells, resulting in loss of beige fat identity without other health changes such as obesity or inflammation. This allowed them to isolate the role of beige fat alone. In these mice, white fat markers increased around blood vessels and led to higher blood pressure and arterial stiffness.
Koenen noted: "We didn't want the model to be analogous to an obese versus lean individual. 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." She added: "We were surprised to find such drastic remodeling of adipose tissue lining the vasculature."
Further analysis showed that without beige fat, vascular cells activated genes promoting fibrous tissue formation and vessel stiffness. The researchers discovered that fluid from beige-fat-deficient cells could trigger this gene activity when applied directly to vascular cells.
Using large-scale genetic data, they identified QSOX1 as an enzyme secreted by these adipocytes when beige identity is lost. Beige fat normally suppresses QSOX1 production; without it, QSOX1 becomes overactive and contributes to vessel remodeling and hypertension. Mice engineered without both Prdm16 and Qsox1 did not develop vascular dysfunction despite lacking beige fat.
The study also found that people with mutations in PRDM16—the same gene studied in mice—tend to have higher blood pressure levels.
This research highlights an obesity-independent pathway where loss of beige fat triggers QSOX1-driven changes leading to high blood pressure. The findings suggest potential new therapeutic targets for hypertension by focusing on molecular interactions between different types of body fat and blood vessels.
Cohen summarized: "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."
