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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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 1

pCF is a unique fat depot that expands with aging and obesity.

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pCF is a unique fat depot that expands with aging and obesity. (A) Repre...
(A) Representative images of pCF on top of hearts from control diet–fed (6 months old), control diet–fed old mice (20 months old), and Western diet–fed mice (6 months old; 12 weeks on a Western diet). Scale bars: 0.5 cm. (B) pCF weight normalized to BW, (C) maximal oxygen consumption (VO2max) during graded maximal exercise testing, and (D) relationship between VO2max and the amount of pCF for control (Ctrl) and old animals. (E) Representative H&E-stained images of the pCF depot from control, old, and Western diet–fed mice. Scale bars: 50 μm. (F) Distribution of multilocular and unilocular adipocytes and (G) unilocular adipocyte size for control and old animals. (H) pCF weight normalized to BW, (I) VO2max during graded maximal exercise testing, and (J) relationship between VO2max and the amount of pCF for control diet–fed and Western diet–fed (WD) animals. (K) Distribution of multilocular and unilocular adipocytes and (L) unilocular adipocyte size for control and Western diet–fed animals. For pCF weight and exercise testing, n = 5–14 per biological animal replicate. For adipocyte quantifications, n = 75–150 for a given biological replicate for adipocyte size and n = 150–275 for adipocyte numbers for a given biological replicate, and n = 3–4 biological replicates per genotype. Data are presented as the mean ± SEM or by dot plot with linear regression. P = 0.05, by Student’s t test.