Paracardial fat remodeling affects systemic metabolism through alcohol dehydrogenase 1
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
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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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 7

The ADH1/retinaldehyde pathway regulates pCF remodeling by altering mitochondria through PGC-1α.

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The ADH1/retinaldehyde pathway regulates pCF remodeling by altering mito...
(A) Representative TEM images of pCF from WT and Adh1-KO mice. L, lipid droplet; N, nucleus. Arrows indicate mitochondria. Scale bars: 2 μm. (B) Measurements of mitochondrial area and (C) aspect ratio from TEM images of pCF from WT and Adh1-KO mice. (D) qPCR for mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), Opa1, and Drp1 mRNA expression in pCF. (E) PGC-1α protein expression in nuclear pCF extracts isolated from WT animals injected systemically with vehicle or retinaldehyde for 6 hours compared with expression in the nuclear protein loading control. (F) Immunofluorescence analysis of PGC-1α (red) in pCF from WT controls or mice treated for 6 hours with retinaldehyde and (G) quantification of PGC-1α–positive nuclei from the immunofluorescence images in F. Original magnification, ×400. (H) qPCR analysis of expression of the indicated genes in pCF following vehicle or retinaldehyde treatment for 6 hours or 24 hours. (I) qPCR analysis of mtDNA abundance in pCF following 24 hours of treatment with retinaldehyde or vehicle control in WT mice. (J) Immunofluorescence analysis of PGC-1α (red) in WT or Adh1-KO pCF and (K) quantification of PGC-1α–positive nuclei in immunofluorescence images of WT or Adh1-KO pCF. (L) qPCR analysis of Opa1 expression in the pCF depot from WT vehicle-treated, Adh1-KO vehicle-treated, and Adh1-KO chronic retinaldehyde–treated mice (1-month-long treatments). (M) qPCR analysis of OPA1 expression in the pCF depot of humans with a BMI below 30 or a BMI of 30 or higher. (N) qPCR quantification of relative mtDNA abundance normalized to nDNA content in the pCF depot of humans with a BMI below or above 30. n = 7–9 per group for human gene expression analysis; n = 3–4 for mitochondrial content measurements; n = 3–5 per group for mouse gene expression analysis; n = 4–6 per group for mouse mitochondrial content measurements; n = 4–8 per group for animal biological replicates for immunostaining quantification; and n ≥65 nuclei analyzed per biological replicate for TEM quantifications. Data are presented as the mean ± SEM for bar graphs. Data were analyzed by Student’s t test when comparing 2 groups or by 1-way ANOVA with Tukey’s HSD multiple-comparison test for comparisons of 3 groups. Asterisks indicate significance compared with the control group, and the pound symbol indicates significance between Adh1-KO vehicle-treated and Adh1-KO chronic retinaldehyde–treated groups at P = 0.05.