Paracardial fat remodeling affects systemic metabolism through alcohol dehydrogenase 1
Jennifer M. Petrosino, … , Ouliana Ziouzenkova, Federica Accornero
Jennifer M. Petrosino, … , Ouliana Ziouzenkova, Federica Accornero
Published February 15, 2021
Citation Information: J Clin Invest. 2021;131(4):e141799. https://doi.org/10.1172/JCI141799.
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Research Article Cardiology Metabolism

Paracardial fat remodeling affects systemic metabolism through alcohol dehydrogenase 1

Abstract

The relationship between adiposity and metabolic health is well established. However, very little is known about the fat depot, known as paracardial fat (pCF), located superior to and surrounding the heart. Here, we show that pCF remodels with aging and a high-fat diet and that the size and function of this depot are controlled by alcohol dehydrogenase 1 (ADH1), an enzyme that oxidizes retinol into retinaldehyde. Elderly individuals and individuals with obesity have low ADH1 expression in pCF, and in mice, genetic ablation of Adh1 is sufficient to drive pCF accumulation, dysfunction, and global impairments in metabolic flexibility. Metabolomics analysis revealed that pCF controlled the levels of circulating metabolites affecting fatty acid biosynthesis. Also, surgical removal of the pCF depot was sufficient to rescue the impairments in cardiometabolic flexibility and fitness observed in Adh1-deficient mice. Furthermore, treatment with retinaldehyde prevented pCF remodeling in these animals. Mechanistically, we found that the ADH1/retinaldehyde pathway works by driving PGC-1α nuclear translocation and promoting mitochondrial fusion and biogenesis in the pCF depot. Together, these data demonstrate that pCF is a critical regulator of cardiometabolic fitness and that retinaldehyde and its generating enzyme ADH1 act as critical regulators of adipocyte remodeling in the pCF depot.

Authors

Jennifer M. Petrosino, Jacob Z. Longenecker, Srinivasagan Ramkumar, Xianyao Xu, Lisa E. Dorn, Anna Bratasz, Lianbo Yu, Santosh Maurya, Vladimir Tolstikov, Valerie Bussberg, Paul M.L. Janssen, Muthu Periasamy, Michael A. Kiebish, Gregg Duester, Johannes von Lintig, Ouliana Ziouzenkova, Federica Accornero

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Figure 2

Importance of Adh1 expression for pCF biology.

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Importance of Adh1 expression for pCF biology. (A) Heatmap and (B) the t...
(A) Heatmap and (B) the top most significantly regulated canonical pathways determined by IPA from a list of 1023 genes that were differentially regulated between WT iVF and pCF using the Affymetrix transcriptome array. (C) Schematic of the retinol oxidation pathway. (D) Western blot and (E) quantification of ADH1 expression normalized to GAPDH and β-actin in the pCF depot of control, old, and Western diet–fed mice. (F) qPCR analysis of Adh1 expression in the pCF depot of control, old, and Western diet–fed mice. (G) qPCR analysis of ADH1 expression in the pCF depot of humans with a BMI below 30 or a BMI of 30 or higher. (H) qPCR analysis of ADH1 expression in the pCF depot of humans aged 30 years or younger and 50 years or older. n = 3 per group for biological animal replicates in the Western blot; n = 4–6 per group for biological animal replicates for qPCR analysis; n = 5 for samples from young and old humans; n = 6–8 for samples from lean and obese humans. Data are presented as the mean ± SEM. *P = 0.05, by Student’s t test for comparisons between 2 groups for human data, or by 1-way ANOVA with Tukey’s HSD multiple-comparison test for comparison of the mean of Western diet–fed mice and old mice with the mean of the control group.