Cold-mediated regulation of systemic retinol transport controls adipose tissue browning

Transformation of white into brown fat ("browning") reduces obesity in many preclinical models and holds great promise as therapeutic concept in metabolic disease. Vitamin A metabolites (retinoids) have been linked to thermogenic programming of adipose tissue (AT), however the physiologic...

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Published inbioRxiv
Main Authors Fenzl, Anna, Kulterer, Oana Cristina, Spirk, Katrin, Mitulović, Goran, Marculescu, Rodrig, Bilban, Martin, Baumgartner-Parzer, Sabina, Kautzky-Willer, Alexandra, Kenner, Lukas, Plutzky, Jorge, Quadro, Loredana, Kiefer, Florian W
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 07.02.2020
Subjects
Adipocytes
Adipose tissue
Cold
Gene expression
Lipid turnover
Lipids
Metabolic disorders
Metabolites
Mitochondria
Protein transport
Retinoids
Thermogenesis
Vitamin A
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Summary:Transformation of white into brown fat ("browning") reduces obesity in many preclinical models and holds great promise as therapeutic concept in metabolic disease. Vitamin A metabolites (retinoids) have been linked to thermogenic programming of adipose tissue (AT), however the physiologic importance of systemic retinoid metabolism for AT browning and adaptive thermogenesis is unknown. Here we show that cold stimulation in mice and humans leads to an increase in circulating retinol and its plasma transporter, retinol binding protein (RBP). Cold exposure shifts retinol abundance from liver towards subcutaneous white AT (sWAT) which correlates with enhanced thermogenic gene expression. Cold-mediated retinoid flux is abrogated in Rbp deficient (Rbp-/-) mice, a model with defective retinoid transport. As a consequence, AT browning and mitochondrial function are dramatically impaired in sWAT, which renders Rbp-/- mice cold intolerant. Rbp deficiency also attenuates cold-induced lipid clearance most likely due to decreased oxidative capacity. In humans, cold-mediated retinol increase is associated with enhanced lipid utilization, and retinol stimulation in primary human adipocytes promotes thermogenic gene expression and mitochondrial respiration. In conclusion, systemic vitamin A abundance is regulated by cold exposure in mice and humans and intact retinoid shuttling is essential for cold-induced AT browning and lipid turnover.
DOI:10.1101/2020.02.07.938688