The biological link between obesity and hypertension, which contributes to cardiovascular disease, has been clarified by a new study. Cardiovascular disease is a leading cause of death globally, with hypertension being a key risk factor.
Research published in Science demonstrates how thermogenic beige fat, a type of adipose tissue distinct from white fat that burns energy, directly influences blood pressure control. The study builds on clinical evidence suggesting individuals with brown fat have a reduced likelihood of hypertension. Researchers developed mouse models unable to form beige fat (the mouse equivalent of adult human brown fat) to observe the effects of its absence. They found that losing beige fat increased the sensitivity of blood vessels to angiotensin II, a significant vasoconstricting hormone. Blocking an enzyme involved in vessel stiffening and signaling disruption was shown to restore healthy vascular function in these mice. These findings suggest a previously unknown mechanism contributing to high blood pressure and indicate potential targets for more precise therapies focusing on fat-blood vessel communication.
Paul Cohen, head of the Weslie R. and William H. Janeway Laboratory of Molecular Metabolism, stated that while the link between obesity and hypertension has been known, the underlying biology was not fully understood. He noted that the specific type of fat, beige fat, influences vascular function and overall blood pressure regulation.
Understanding Different Fat Types
Brown fat, found in newborns and some adults, burns energy and generates heat, unlike white fat, which stores calories. Previous work from Cohen's lab indicated that individuals with more brown fat had significantly lower odds of hypertension and other cardiometabolic disorders. However, this clinical data only established correlation, necessitating lab experiments to determine causation and mechanisms.
Mascha Koenen, a postdoctoral fellow in the Cohen lab, highlighted the lack of mechanistic understanding behind the link between thermogenic adipose tissue (brown fat) and hypertension.
Experimental Design and Findings
To investigate, the team engineered mouse models that were healthy except for a complete loss of beige fat identity. This was achieved by deleting the Prdm16 gene specifically in fat cells, isolating the beige fat variable from other factors like obesity or inflammation. This ensured the engineered mice represented healthy individuals lacking brown fat.
This genetic modification led to significant changes. The fat surrounding the blood vessels in these mice began exhibiting markers of white fat, including angiotensinogen, a precursor to a blood pressure-increasing hormone. The mice developed elevated blood pressure and mean arterial pressure. Tissue analysis showed the accumulation of stiff, fibrous tissue around the vessels. Arteries from these animals also displayed heightened sensitivity to angiotensin II, a potent blood pressure signal.
Koenen expressed surprise at the extent of remodeling observed in the adipose tissue lining the vasculature.
Single-nucleus RNA sequencing revealed that in the absence of beige fat, vascular cells activated a gene program promoting stiff, fibrous tissue, which reduces vessel flexibility and increases heart workload and blood pressure. The team identified that secreted mediators from beige fat-deficient cells could activate these fibrous tissue-promoting genes in vascular cells.
Utilizing gene and protein expression datasets, the researchers identified QSOX1, an enzyme previously linked to tissue remodeling in cancer, as a key factor. Beige fat typically suppresses QSOX1 production; however, when beige fat identity is lost, QSOX1 is overproduced, initiating a cascade of events leading to hypertension. To confirm QSOX1's role, mice engineered to lack both Prdm16 and Qsox1 did not develop beige fat or vascular dysfunction, as predicted.
Conclusion and Implications
These findings establish an obesity-independent signaling pathway where the loss of beige fat identity results in the release of QSOX1, which in turn causes harmful remodeling of blood vessels and elevated blood pressure. Data from large clinical cohorts also indicate that individuals with PRDM16 mutations (the same gene whose loss activates QSOX1 in mice) exhibit higher blood pressure, suggesting the findings are relevant to humans.
This study exemplifies "reverse translation," where observations from human patients drive mechanistic experimentation in the lab. This iterative process identified a new molecular entry point for understanding and potentially treating hypertension. The results could lead to further research into how QSOX1 remodels perivascular scaffolding and affects angiotensin receptors, as well as how differences in perivascular fat influence disease development. The findings also suggest potential future therapeutic strategies for hypertension, including targeting QSOX1, allowing for more individualized medical approaches based on patient characteristics.