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 4

pCF regulates circulating metabolites and cardiometabolic fitness.

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pCF regulates circulating metabolites and cardiometabolic fitness. (A) M...
(A) Metabolomics pathway analysis of differentially regulated metabolites in plasma from 4-month-old WT and Adh1-KO. (B) Heatmap of top 20 significantly different metabolites in the plasma of WT and Adh1-KO animals. (C) List of metabolites that correlate with fatty acid biosynthesis. (D) Representative schematic of pCF removal (Rmv) and sham surgeries. (E) BW, (F) echocardiographic percentage of fractional shortening, (G) heart rate, and (H) blood pressure measurements after sham or pCF removal surgery in 4-month-old WT and Adh1-KO mice. (I–L) Relative levels of top metabolites implicated in fatty acid biosynthesis in WT and Adh1-KO plasma following sham or pCF removal surgery. (M) Time until exhaustion and (N) VO2max during graded maximal exercise testing. (O) RER during graded maximal exercise testing for the WT and Adh1-KO sham-operated and pCF removal groups. (P) Carbohydrate oxidation during graded exercise testing for WT and Adh1-KO sham-operated and pCF removal groups. n = 4–7 per group for biological animal replicates. Data are presented as the mean ± SEM for bar graphs, as dot plots indicating the mean over the course of a test, as 2D area charts for oxidation graphs, or as box-and-whisker plots. Data were analyzed by Student’s t test for comparisons between 2 groups or by 2-way ANOVA with Tukey’s HSD multiple-comparison test for consideration of both treatments and genotypes. Asterisks indicate significance between genotypes of the same group (sham-operated, pCF removal), and the pound signs indicate significance within the same genotype but with different treatments, at P = 0.05.