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SciencePhysiologyPeer-reviewed journal article

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

Mascha KoeneniD, Tobias BecheriD, Giulia PaganoiD, Ilaria Del GaudioiD, Jorge A. BarreroiD, Augusto C. I. MontezanoiD, Jenelys Ruiz OrtiziD, Zeran LiniD, Nicolás Gómez-BanoyiD, Rose AmblardiD, Daniel SchrieveriD, Meltem Ece KarsiD, Luisa Rubinelli, Sarah J HalixiD, Zhen Fang Huang CaoiD, Xing ZengiD, Scott D. Butler, Yuval ItaniD, Rhian M. TouyziD, Annarita Di LorenzoiD, Paul CoheniD

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Abstract

While excess adiposity is a major risk factor for hypertension and cardiovascular disease, brown fat is associated with protection from these pathologies. Whether brown fat has a causal role in this process and the underlying molecular mechanisms remain unknown. Here we investigate the role of murine beige fat, as a model of inducible brown fat in humans, in adipocyte-vascular crosstalk. Using mice with an adipocyte-specific deletion of PRDM16, resulting in a loss of beige adipocyte identity, we discover a dramatic remodeling of perivascular adipose tissue, increased vascular reactivity and elevated blood pressure. We further show that the circulating enzyme Qsox1 is de-repressed in Prdm16-deficient adipocytes, and deletion of Qsox1 in PRDM16cKO mice rescues vascular fibrosis and reactivity. These results demonstrate a key new role for beige adipocytes in blood pressure regulation and identify Qsox1 as an important mediator of adipocyte-vascular crosstalk.

In-depth summary

Claude Opus 5.5 · xhigh effort · 5 Nov 2026 · from the full text of version 1 (17 Jun 2025) · CC BY-NC 4.0

Adipocyte-specific deletion of Prdm16 ablates beige fat identity, derepresses the secreted enzyme Qsox1, and induces vascular fibrosis, angiotensin II hyperreactivity, and elevated blood pressure in mice.

Brown and beige adipose tissues are associated with lower hypertension risk in humans, but whether beige fat causally regulates blood pressure and through what molecular mediators remained unknown. Using adipocyte-specific Prdm16 and Qsox1 knockout mice alongside human cohorts, this work identifies an adipocyte-to-vascular smooth muscle axis mediated by secreted QSOX1.

Key results

  1. ShownAdipocyte-specific Prdm16 ablation (PRDM16cKO) whitens perivascular adipose tissue (PVAT) and increases mesenteric artery vasoconstriction in response to angiotensin II (ANGII) without raising circulating ANGII.

    PRDM16cKO mice lost multilocular lipid droplets and thermogenic markers (Ucp1, Cpn2, Cox8b) while upregulating white fat markers (Aldh3b2, Reep6, Agt) in thoracic and abdominal PVAT without body weight change or elevated serum AGT/plasma ANGII (n=8 per group), and PVAT-denuded mesenteric arteries showed increased ANGII-mediated contraction (n=4-5 per group). · PRDM16-dependent adipocyte remodeling regulates…; Figure legends

  2. ShownSingle-nucleus RNA sequencing (snucRNASeq) of mesenteric PVAT shows that Prdm16 loss remodels mature adipocyte subpopulations toward lipogenic and pro-fibrotic profiles without altering immune cell proportions.

    Across 13,164 nuclei (15 cell types, including 8,783 mature adipocyte nuclei in 7 subclusters), PRDM16cKO changed 4 of 7 adipocyte subclusters, increasing lipogenic clusters (Ad5, Ad6) and reducing lipolytic, anti-oxidative, and adipokine-expressing clusters (Ad0, Ad1) by ~50%. · Loss of Prdm16 results in mesenteric adipocyte…; Figure legends

  3. ShownBeige adipocyte ablation causes arterial fibrosis and elevates systemic blood pressure in mice, paralleling PRDM16 variant associations and cardiac remodeling in humans lacking brown fat.

    PRDM16cKO mice showed increased mesenteric artery and aortic fibrosis and higher systolic, diastolic, and mean arterial BP over 3 weeks of radiotelemetry (n=28-29/group); in humans, PRDM16 exon 9 coding variants associated with BP and hypertension in UK Biobank (n=180,500) and Mount Sinai cohorts (n=21,680 EUR; n=19,856 AFR), and BAT- patients (n=1,095 vs 653 BAT+) had higher LV mass and LA volume indices. · Loss of beige adipocytes leads to vascular…; Figure legends

  4. ShownPrdm16 deficiency derepresses the adipocyte-secreted sulfhydryl oxidase Qsox1, and simultaneous adipocyte deletion of Qsox1 and Prdm16 rescues aortic extracellular matrix (ECM) expression and ANGII hypercontraction.

    Overlaying PVAT differentially expressed genes with adipocyte secretome data identified 12 signal-peptide-positive PRDM16-regulated secreted proteins including Qsox1; double knockout (DFcKO) mice retained whitened PVAT and elevated local AGT but normalized aortic ECM gene expression (Fn1, Col1a1, Col3a1, Col4a1) and completely rescued mesenteric artery ANGII contraction (n=5 per group). · An adipocyte-derived secreted factor is…; Qsox1 is required to provoke vascular…; Figure legends

Methods, data and reproducibility

Generated adipocyte-specific Prdm16cKO, Qsox1cKO, and Prdm16/Qsox1 double-knockout (DFcKO) mice and assessed PVAT remodeling, mesenteric artery pressure myography, radiotelemetric blood pressure, bulk RNA-seq, and snucRNASeq. Evaluated human PRDM16 coding variants in biobanks, echocardiograms in a brown fat cohort, and primary adipocyte-to-vascular smooth muscle cell conditioned media transfer.

  • Thoracic, abdominal, and mesenteric PVAT and arteries from Prdm16cKO, Qsox1cKO, DFcKO, and floxed littermate control mice (bulk RNA-seq, snucRNASeq, myography, radiotelemetry) · mouse · n = 13,164 mPVAT nuclei (8,783 adipocyte); n=28-29/group telemetry; n=4-10 assays
  • UK Biobank (UKBB) cohort for PRDM16 exon 9 variant association analysis · human · n = 180,500 individuals
  • Mount Sinai Million Health Discoveries Program European (MSM-EUR) and African (MSM-AFR) ancestry cohorts · human · n = 21,680 EUR individuals; 19,856 AFR individuals
  • Propensity-matched human brown adipose tissue echocardiogram cohort · human · n = 653 BAT+ patients and 1,095 BAT- patients
Methods & tools
SAS software
Reproducibility gaps
No accession numbers or repository links for the bulk RNA-seq, single-nucleus RNA-seq, or analysis code are provided in the text.
Limitations (1)
  • The exact downstream molecular mechanism by which adipocyte-derived QSOX1 alters vascular smooth muscle cell reactivity (such as potential disulfide bond modification on the angiotensin receptor or regulation of reactive oxygen species) was not directly tested (S8). · stated by the authors

Read this if you study adipose-vascular crosstalk, thermogenic beige fat physiology, or molecular mechanisms linking perivascular adipose tissue remodeling to hypertension.

Citations
17
FWCI
84.94
Field percentile
top 1%

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