RDH1 suppresses adiposity by promoting brown adipose adaptation to fasting and re-feeding

Krois, Charles R.; Vučković, Marta; Huang, Priscilla; Zaversnik, Claire; Liu, Conan S.; Gibson, Candice E.; Wheeler, Madelyn R.; Obrochta, Kristin M.; Min, Jin Hong; Herber, Candice B.; Thompson, Airlia C. S.; Shah, Ishan; Gordon, Sean P.; Hellerstein, Marc K.; Napoli, Joseph L.

doi:10.1007/s00018-019-03046-z

Cited by 18 publications

(14 citation statements)

References 92 publications

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“…Rdh1 has widespread tissue expression, but neither muscle or nor epidydymal white fat pads express rdh1. Brown adipose tissue (BAT) expresses rdh1 more intensely than most other tissues, and rdh1-null mice have an average body temperature ~0.8 °C lower than WT under normal vivarium conditions (Krois et al, 2019). These data indicate flawed BAT function.…”

Section: Functions Of Mrdh1/hrdh16mentioning

confidence: 99%

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Post-natal all-trans-retinoic acid biosynthesis

Napoli

2020

Methods in Enzymology

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Generation of the autacoid all-trans-retinoic acid (ATRA) from retinol (vitamin A) relies on a complex metabolon that includes retinol binding-proteins and enzymes from the short-chain dehydrogenase/reductase and aldehyde dehydrogenase gene families. Serum retinol bindingprotein delivers all-trans-retinol (vitamin A) from blood to cells through two membrane receptors, Stra6 and Rbpr2. Stra6 and Rbpr2 convey retinol to cellular retinol binding-protein type 1 (Crbp1). Holo-Crbp1 delivers retinol to lecithin:retinol acyl transferase (Lrat) for esterification and storage. Lrat channels retinol directly into its active site from holo-Crbp1 by protein-protein interaction. The ratio apo-Crbp1/holo-Crbp1 directs flux of retinol into and out of retinyl esters, through regulating esterification vs ester hydrolysis. Multiple retinol dehydrogenases (Rdh1, Rdh10, Dhrs9, Rdhe2, Rdhe2s) channel retinol from holo-Crbp1 to generate retinal for ATRA biosynthesis. β-Carotene oxidase type 1 generates retinal from carotenoids, delivered by the scavenger receptor-B1. Retinal reductases (Dhrs3, Dhrs4, Rdh11) reduce retinal into retinol, thereby restraining ATRA biosynthesis. Retinal dehydrogenases (Raldh1, 2, 3) dehydrogenate retinal irreversibly into ATRA. ATRA regulates its own concentrations by inducing Lrat and ATRA degradative enzymes. ATRA exhibits hormesis. Its effects relate to its concentration as an inverted J-shaped curve, transitioning from beneficial in the "goldilocks" zone to toxicity, as concentrations increase. Hormesis has distorted understanding physiological effects of ATRA post-nataly using chow-diet fed, ATRA-dosed animal models. Cancer, immune deficiency and metabolic abnormalities result from mutations and/or insufficiency in Crbp1 and retinoid metabolizing enzymes. RA6) and Rbpr2 (Rbp receptor 2). Cellular retinol binding-protein type 1 (Crbp1) and lecithin:retinol acyl transferase (Lrat) guarantee that retinol flux into cells occurs one way physiologically. Crbp1 sequesters retinol, preventing its exit from cells, and delivers retinol to Lrat. Lrat, which synthesizes retinyl esters, accesses retinol bound to Crbp1 and channels retinol directly into its active site by protein-protein interaction. A second esterifying enzyme, diacylglycerol acyltransferase type 1 (Dgat1) also can synthesize retinyl esters, especially in skin, but does not make a major contribution in most cells. The ratio apo-Crbp1/holo-Crbp1 directs flux of retinol into and out of retinyl esters, through stimulation of

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Section: Functions Of Mrdh1/hrdh16mentioning

confidence: 99%

“…Mouse kidney and skin have the highest rdh1 mRNA (Krois et al, 2019). Accordingly, the human ortholog rdh16 contributes to ATRA biosynthesis in human skin (Pavez Loriè, Chamcheu, Vahlquist, & Törmä, 2009;Pavez Loriè, Li, Vahlquist, & Törmä, 2009).…”

Section: Functions Of Mrdh1/hrdh16mentioning

confidence: 99%

Post-natal all-trans-retinoic acid biosynthesis

Napoli

2020

Methods in Enzymology

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“…Lower ATRA levels in BAT are linked to defects in cold-induced thermogenesis in lipocalin 2 knockout mice [17]. Genetic ablation of retinol dehydrogenases involved in ATRA synthesis results in increased adiposity and defects in BAT thermogenesis in mice [18,19]. Further, mice with blunted retinoic acid receptor (RAR) signaling in the liver—owing to liver-specific transgenic expression of a dominant negative form of RARα—show decreased hepatic FAO and develop liver steatosis [20].…”

Section: Introductionmentioning

confidence: 99%

Novel Markers of the Metabolic Impact of Exogenous Retinoic Acid with A Focus on Acylcarnitines and Amino Acids

Ribot

Arreguín

Kuda

et al. 2019

IJMS

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Treatment with all-trans retinoic acid (ATRA), the carboxylic form of vitamin A, lowers body weight in rodents by promoting oxidative metabolism in multiple tissues including white and brown adipose tissues. We aimed to identify novel markers of the metabolic impact of ATRA through targeted blood metabolomics analyses, with a focus on acylcarnitines and amino acids. Blood was obtained from mice treated with a high ATRA dose (50 mg/kg body weight/day, subcutaneous injection) or placebo (controls) during the 4 days preceding collection. LC-MS/MS analyses with a focus on acylcarnitines and amino acids were conducted on plasma and PBMC. Main results showed that, relative to controls, ATRA-treated mice had in plasma: increased levels of carnitine, acetylcarnitine, and longer acylcarnitine species; decreased levels of citrulline, and increased global arginine bioavailability ratio for nitric oxide synthesis; increased levels of creatine, taurine and docosahexaenoic acid; and a decreased n-6/n-3 polyunsaturated fatty acids ratio. While some of these features likely reflect the stimulation of lipid mobilization and oxidation promoted by ATRA treatment systemically, other may also play a causal role underlying ATRA actions. The results connect ATRA to specific nutrition-modulated biochemical pathways, and suggest novel mechanisms of action of vitamin A-derived retinoic acid on metabolic health.

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“…Rdh1-null mice had lower body temperatures and a lower expression of Ucp1 in BAT. Mechanistically, Rdh1-deficiency resulted in decreased all-trans retinoic acid levels in BAT levels after refeeding which impaired lipolysis that is crucial for proper BAT function (55).…”

Section: Retinoids and Transcriptional Control Of The Thermogenic Promentioning

confidence: 99%

The Transcriptional Role of Vitamin A and the Retinoid Axis in Brown Fat Function

Herz

Kiefer

2020

Front. Endocrinol.

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In recent years, brown adipose tissue (BAT) has gained significance as a metabolic organ dissipating energy through heat production. Promotion of a thermogenic program in fat holds great promise as potential therapeutic tool to counteract weight gain and related sequelae. Current research efforts are aimed at identifying novel pathways regulating brown fat function and the transformation of white adipocytes into BAT-like cells, a process called "browning." Besides numerous genetic factors some circulating molecules can act as mediators of adipose tissue thermogenesis. Vitamin A metabolites, the retinoids, are potent regulators of gene transcription through nuclear receptor signaling and are thus involved in a plethora of metabolic processes. Accumulating evidence links retinoid action to brown fat function and browning of WAT mainly via orchestrating a transcriptional BAT program in adipocytes including expression of key thermogenic genes such as uncoupling protein 1. Here we summarize the current understanding how retinoids play a role in adipose tissue thermogenesis through transcriptional control of thermogenic gene cassettes and potential non-genomic mechanisms.

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RDH1 suppresses adiposity by promoting brown adipose adaptation to fasting and re-feeding

Cited by 18 publications

References 92 publications

Post-natal all-trans-retinoic acid biosynthesis

Post-natal all-trans-retinoic acid biosynthesis

Novel Markers of the Metabolic Impact of Exogenous Retinoic Acid with A Focus on Acylcarnitines and Amino Acids

The Transcriptional Role of Vitamin A and the Retinoid Axis in Brown Fat Function

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