Ablation of Prdm16 and beige fat identity causes vascular remodeling and elevated blood pressure.

Adipocyte-specific Prdm16 knockout mice exhibit elevated blood pressure compared to controls.

• Mice with adipocyte-specific deletion of Prdm16 (Prdm16-AKO) showed significantly elevated systolic and diastolic blood pressure.
• Blood pressure was measured using telemetry to ensure accurate, stress-free recordings.
• The hypertensive phenotype was observed under standard housing conditions without additional metabolic challenge.
• This finding establishes a causal link between loss of beige adipocyte identity and hypertension.

Loss of Prdm16 in adipocytes leads to marked remodeling of perivascular adipose tissue (PVAT) and increased vascular reactivity.

• Prdm16-AKO mice displayed structural remodeling of PVAT surrounding blood vessels.
• Vascular reactivity was increased in Prdm16-AKO mice, indicating altered vascular tone regulation.
• The remodeling of PVAT was associated with changes in the adipocyte-vascular cross-talk axis.
• These vascular changes are consistent with a pro-hypertensive phenotype driven by loss of beige fat identity.

QSOX1 (Quiescin Sulfhydryl Oxidase 1) is derepressed in Prdm16-deficient adipocytes and circulates at elevated levels.

• QSOX1 expression was upregulated in adipocytes lacking Prdm16, identifying it as a secreted factor regulated by beige adipocyte identity.
• QSOX1 is described as a 'circulating enzyme' that mediates communication between adipose tissue and the vasculature.
• Normally, Prdm16 activity in beige adipocytes represses QSOX1 expression, and loss of this repression leads to elevated circulating QSOX1.
• This identifies QSOX1 as a novel adipokine involved in adipocyte-vascular cross-talk.

Deletion of Qsox1 in Prdm16 conditional knockout mice prevented vascular fibrosis and normalized vascular reactivity.

• Double knockout mice lacking both Prdm16 (in adipocytes) and Qsox1 were generated to test the causal role of QSOX1.
• Vascular fibrosis observed in Prdm16-AKO mice was prevented upon additional deletion of Qsox1.
• Vascular reactivity was normalized in the double knockout animals compared to Prdm16-AKO mice.
• These genetic rescue experiments establish QSOX1 as a key downstream mediator of the vascular pathology caused by loss of beige adipocyte identity.

Brown/beige fat is associated with protection from cardiovascular pathology, but the relationship between beige fat and blood pressure regulation was previously unknown to be causal.

• Prior studies had shown associations between brown fat activity and protection from cardiovascular disease without establishing causality.
• This study uses mouse beige fat 'as a model of human inducible brown fat' to investigate adipocyte-vascular cross-talk.
• Excess adiposity is described as 'a major risk factor for hypertension and heart disease.'
• The study design with adipocyte-specific knockout mice was chosen to directly test the causal role of beige adipocytes in blood pressure regulation.

QSOX1 is identified as an important mediator of adipocyte-vascular cross-talk downstream of Prdm16-dependent beige adipocyte identity.

• QSOX1 functions as the molecular link between beige adipocyte dysfunction and vascular pathology in this model.
• The identification of QSOX1 provides a potential therapeutic target for hypertension associated with adipose tissue dysfunction.
• QSOX1 mediates both vascular fibrosis and altered vascular reactivity in the context of Prdm16 deficiency.
• The authors conclude that these results 'identify QSOX1 as an important mediator of adipocyte-vascular cross-talk.'