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Pericardial Adipose Tissue Regulates Cardiac Remodeling via Lipolysis-Mediated CD206+ Macrophage Expansion [snRNA-seq]

ABSTRACT: Obesity is a major risk factor for heart failure (HF). Recent clinical studies suggest an association between pericardial adipose tissue (PeAT) volume and HF, yet the underlying mechanisms remain elusive. Here, we demonstrate that impaired lipolysis in PeAT of obese mice exacerbates cardiac remodeling under pressure overload. High-fat diet (HFD) feeding doubled PeAT volume in mice and accelerated cardiac fibrosis and dysfunction after transverse aortic constriction (TAC). PeAT removal prevented the cardiac remodeling in HFD mice, whereas PeAT transplantation from obese mice to lean mice recapitulated the adverse cardiac phenotype. In HFD mice, TGF-β1 was elevated in PeAT with increased downstream SMAD2 activation in adjacent myocardium. Single-nucleus transcriptomics identified CD206+ macrophages as the primary TGF-β1 source in PeAT from both HFD mice and HF patients. Three-dimensional imaging revealed sympathetic denervation in PeAT of obese mice, accompanied by impaired β3-adrenergic receptor-mediated lipolysis signaling, resulting in reduced local free fatty acid (FFA) availability that promoted CD206+ macrophage expansion. Intrapericardial TGF-β1 neutralization ameliorated cardiac remodeling in HFD mice, and further, restoring β3-adrenergic signaling in PeAT increased local FFA levels, suppressed SMAD2 activation in the heart, and improved cardiac function after TAC. These findings establish a mechanistic link between PeAT dysfunction and HF progression in obesity, highlighting PeAT as a potential therapeutic target.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE295609 | GEO | 2026/09/16

REPOSITORIES: GEO

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Project description:Abstract Aim: Circulating triglyceride and triglyceride-rich lipoprotein (TRL) accumulation is increasingly recognized as a residual atherosclerotic risk, but their specific effect in cardiac remodeling and heart failure (HF) remain largely unexplored. Here we investigated this issue in Gpihbp1 knockout (KO) mice, which develop severe hyperchylomicronemia due to disruption of intravascular TRL hydrolysis . Methods: Cardiac lipid metabolism and remodeling were evaluated in 10-month-old Gpihbp1 KO mice and wild-type littermates under physiological conditions. Mice were also subjected to transverse aortic constriction (TAC) to evaluate the impact of severe hyperchylomicronemia on pressure overload-induced remodeling and HF. Furthermore, Gpihbp1 KO mice were crossed into Ldlr KO background to study hyperchylomicronemia’s effects on hemorheology and high-fat diet (HFD)-induced cardiac pathology. Results: Untargeted cardiac lipidomics revealed 214 differentially regulated lipid species specifically enriched in glycerophospholipids, fatty acid (FA) and diacylglycerol subclasses. qPCR confirmed down-regulated FA oxidation genes and upregulated glucose utilization genes. Electron microscopy showed swollen mitochondria with fragmented cristae, and RNA-seq demonstrated reduced respiratory-chain gene expression. These derangements culminated in impaired cardiac contractile performance in 10-month-old Gpihbp1 KO mice without inducing hypertrophy or fibrosis. After TAC, Gpihbp1 KO hearts exhibited exaggerated diastolic dysfunction, increased myocyte hypertrophy, and fibrosis. In Gpihbp1/Ldlr double knockout (dKO) mice, reduced erythrocyte deformability and increased whole blood viscosity were observed and worsened post-HFD. Additionally, HFD feeding precipitated significant diastolic impairment, cardiac hypertrophy and fibrosis in dKO mice. Conclusion: Severe hyperchylomicronemia due to GPIHBP1 deficiency sensitizes the heart to pathological remodeling and HF. These findings indicate a potential pathogenic contribution of HTG and TRL accumulation to cardiac disease.

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Pericardial Adipose Tissue Regulates Cardiac Remodeling via Lipolysis-Mediated CD206+ Macrophage Expansion [snRNA-seq]

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