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 3

Adh1 deficiency drives pCF accumulation and impairments in cardiometabolic fitness.

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Adh1 deficiency drives pCF accumulation and impairments in cardiometabo...
(A) Representative image of hearts with pCF from 4-month-old WT and Adh1-KO mice. (B and C) pCF and heart weights normalized to BW and (D) BW of the mice. (E and F) Measurements of lean mass and fat mass in WT and Adh1-KO mice using the total body EchoMRI analyzer. (G) Representative H&E-stained images of the pCF depot from WT and Adh1-KO mice. Scale bars: 100 μm. (H) Distribution of multilocular and unilocular adipocytes and (I) unilocular adipocyte size in WT and Adh1-KO animals. (J) Food intake over a 24-hour period and (K) activity (XYZ; blue box indicates the awake period) for WT and Adh1-KO animals. (L) Overnight fasting glucose and (M) average 24-hour oxygen consumption and CO2 production in WT and Adh1-KO animals. (N) VO2max (maximal oxygen consumption), (O)RER (a measure of fuel substrate use), (P) carbohydrate (Cho) oxidation, and (Q) time until exhaustion during graded maximal exercise testing. n = 4–15 per group for biological animal replicates; n = 160–800 cells for adipocyte quantification; and 50–100 cells for adipocyte size quantification for each biological replicate. Data are presented as the mean ± SEM for the bar graphs. The dots in K and O indicate the mean points over the course of a test. *P = 0.05, by Student’s t test.