retinaldehyde and Obesity

In this review, we summarize recent advances in understanding vitamin A-dependent regulation of sex-specific differences in metabolic diseases, inflammation, and certain cancers. We focus on the characterization of the aldehyde dehydrogenase-1 family of enzymes (ALDH1A1, ALDH1A2, ALDH1A3) that catalyze conversion of retinaldehyde to retinoic acid. Additionally, we propose a "horizontal transfer of signaling" from estrogen to retinoids through the action of ALDH1A1. Although estrogen does not directly influence expression of Aldh1a1, it has the ability to suppress Aldh1a2 and Aldh1a3, thereby establishing a female-specific mechanism for retinoic acid generation in target tissues. ALDH1A1 regulates adipogenesis, abdominal fat formation, glucose tolerance, and suppression of thermogenesis in adipocytes; in B cells, ALDH1A1 plays a protective role by inducing oncogene suppressors Rara and Pparg. Considering the conflicting responses of Aldh1a1 in a multitude of physiological processes, only tissue-specific regulation of Aldh1a1 can result in therapeutic effects. We have shown through successful implantation of tissue-specific Aldh1a1-/- preadipocytes that thermogenesis can be induced in wild-type adipose tissues to resolve diet-induced visceral obesity in females. We will briefly discuss the emerging role of ALDH1A1 in multiple myeloma, the regulation of reproduction, and immune responses, and conclude by discussing the role of ALDH1A1 in future therapeutic applications.

Topics: Adipocytes; Adipogenesis; Adipose Tissue, White; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase 1 Family; Animals; Body Fat Distribution; Chronic Disease; Cytokines; Diet; Disease Models, Animal; Estradiol; Female; Humans; Obesity; Polycystic Ovary Syndrome; Retinal Dehydrogenase; Retinaldehyde; Risk Factors; Sex Factors; Thermogenesis; Tretinoin

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.

Topics: Adipose Tissue; Alcohol Dehydrogenase; Animals; Cell Nucleus; Metabolomics; Mice; Mice, Knockout; Mitochondria, Heart; Obesity; Pericardium; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Retinaldehyde; Signal Transduction

Maternal vitamin A intake varies but its impact on offspring metabolic health is unknown. Here we found that maternal vitamin A or retinoic acid (RA) administration expanded PDGFRα

Topics: Adipogenesis; Adipose Tissue, Beige; Animals; Body Temperature; Cells, Cultured; Chromatography, High Pressure Liquid; Diet, High-Fat; Dietary Supplements; Female; Glucose Tolerance Test; Male; Mice; Mice, Inbred C57BL; Obesity; Oxygen Consumption; Pregnancy; Receptor, Platelet-Derived Growth Factor alpha; Retinaldehyde; Signal Transduction; Stromal Cells; Tretinoin; Vascular Endothelial Growth Factor A; Vitamin A

The roles of vitamin A (VA) in the development of metabolic diseases remain unanswered. We have reported that retinoids synergized with insulin to induce the expression of sterol-regulatory element-binding protein 1c gene (Srebp-1c) expression in primary rat hepatocytes. Additionally, the hepatic Srebp-1c expression is elevated in Zucker fatty (ZF) rats, and reduced in those fed a VA deficient diet. VA is metabolized to retinoic acid (RA) for regulating gene expression. We hypothesized that the expression of RA production enzymes contributes to the regulation of the hepatic Srebp-1c expression. Therefore, we analyzed their expression levels in Zucker lean (ZL) and ZF rats. The mRNA levels of retinaldehyde dehydrogenase family 1 gene (Raldh1) were found to be higher in the isolated and cultured primary hepatocytes from ZF rats than that from ZL rats. The RALDH1 protein level was elevated in the liver of ZF rats. Retinol and retinal dose- and time-dependently induced the expression of RA responsive Cyp26a1 gene in hepatocytes and hepatoma cells. INS-1 cells were identified as an ideal tool to study the effects of RA production on the regulation of gene expression because only RA, but not retinal, induced Srebp-1c mRNA expression in them. Recombinant adenovirus containing rat Raldh1 cDNA was made and used to infect INS-1 cells. The over-expression of RALDH1 introduced the retinal-mediated induction of Srebp-1c expression in INS-1 cells. We conclude that the expression levels of the enzymes for RA production may contribute to the regulation of RA responsive genes, and determine the responses of the cells to retinoid treatments. The elevated hepatic expression of Raldh1 in ZF rats may cause the excessive RA production from retinol, and in turn, result in higher Srebp-1c expression. This excessive RA production may be one of the factors contributing to the elevated lipogenesis in the liver of ZF rats.

Topics: Aldehyde Dehydrogenase 1 Family; Animals; Cell Line; Cytochrome P-450 Enzyme System; Gene Expression Regulation; Hepatocytes; Lipogenesis; Liver; Male; Obesity; Rats; Rats, Zucker; Retinal Dehydrogenase; Retinaldehyde; Retinoic Acid 4-Hydroxylase; RNA, Messenger; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Tretinoin; Vitamin A

The metabolism of vitamin A and the diverse effects of its metabolites are tightly controlled by distinct retinoid-generating enzymes, retinoid-binding proteins and retinoid-activated nuclear receptors. Retinoic acid regulates differentiation and metabolism by activating the retinoic acid receptor and retinoid X receptor (RXR), indirectly influencing RXR heterodimeric partners. Retinoic acid is formed solely from retinaldehyde (Rald), which in turn is derived from vitamin A. Rald currently has no defined biologic role outside the eye. Here we show that Rald is present in rodent fat, binds retinol-binding proteins (CRBP1, RBP4), inhibits adipogenesis and suppresses peroxisome proliferator-activated receptor-gamma and RXR responses. In vivo, mice lacking the Rald-catabolizing enzyme retinaldehyde dehydrogenase 1 (Raldh1) resisted diet-induced obesity and insulin resistance and showed increased energy dissipation. In ob/ob mice, administrating Rald or a Raldh inhibitor reduced fat and increased insulin sensitivity. These results identify Rald as a distinct transcriptional regulator of the metabolic responses to a high-fat diet.

Topics: 3T3-L1 Cells; Adipogenesis; Animals; Diet; Female; Growth Inhibitors; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; NIH 3T3 Cells; Obesity; Rabbits; Retinaldehyde