Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.
Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA.
J Clin Invest. 2021 Feb 15;131(4). doi: 10.1172/JCI141799.
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.
肥胖与代谢健康之间的关系已得到充分证实。然而，人们对位于心脏上方和周围的脂肪组织——心外膜脂肪（pCF）知之甚少。在这里，我们表明 pCF 会随着衰老和高脂肪饮食而发生重塑，并且该脂肪库的大小和功能受醇脱氢酶 1（ADH1）的控制，ADH1 将视黄醇氧化为视黄醛。老年人和肥胖人群的 pCF 中 ADH1 表达水平较低，在小鼠中，Adh1 的基因缺失足以驱动 pCF 积累、功能障碍以及代谢灵活性的全面受损。代谢组学分析显示，pCF 控制着影响脂肪酸生物合成的循环代谢物水平。此外，手术切除 pCF 库足以挽救 Adh1 缺陷型小鼠中观察到的心脏代谢灵活性和适应性受损。此外，用视黄醛治疗可防止这些动物的 pCF 重塑。从机制上讲，我们发现 ADH1/视黄醛途径通过驱动 PGC-1α 核易位并促进 pCF 库中线粒体融合和生物发生来发挥作用。总之，这些数据表明 pCF 是心脏代谢适应性的关键调节剂，而视黄醛及其生成酶 ADH1 是 pCF 库中脂肪细胞重塑的关键调节剂。
