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

Abstract

22Browning of white fat reduces obesity in many preclinical models. Vitamin A metabolites 23 (retinoids) have been linked to thermogenic programming of adipose tissue (AT), however 24 the physiologic importance of systemic retinoid metabolism for AT browning is unknown. 25Here we show that cold stimulation in mice and humans increases circulating retinol and its 26 plasma transporter, retinol binding protein (RBP). Cold exposure shifts retinol abundance 27 from liver towards subcutaneous white AT which correlates with enhanced thermogenic gene 28 transcription. Cold-mediated retinoid flux is abrogated in Rbp deficient (Rbp -/-) mice and AT 29 browning is dramatically impaired, which renders Rbp -/mice cold intolerant. Rbp deficiency 30 attenuates cold-induced lipid clearance due to decreased oxidative capacity. In humans, 31 cold-mediated retinol increase is associated with enhanced lipid utilization. Retinol 32 stimulation in primary human adipocytes promotes thermogenic gene expression and 33 mitochondrial respiration. In conclusion, coordinated retinol delivery is essential for cold-34 induced thermogenic programming of white fat. 35 36 7 or exposed to cold (4°C) for 24 hrs. In contrast to WT mice, plasma retinol was barely 124 detectable in Rbp -/mice, as expected (Quadro et al., 1999), and did not increase with cold 125 exposure ( Fig. 2a). Unlike WT controls, retinol concentrations in Rbp-deficient liver and 126 sWAT were not affected by cold challenge (Fig. 2b,c). In contrast, Rbp deficiency did not 127 prevent a cold-induced increase in retinol levels in BAT and gWAT ( Fig. 2d,e). Together, 128these findings indicate that Rbp action is required for cold-induced retinol redistribution 129 between liver and subcutaneous adipose tissue. 130 131 Intact retinol transport is vital for WAT browning.132 Using this Rbp -/mouse model provided a unique tool to study the effects of perturbed retinol 133 delivery on cold-mediated WAT browning. Cold-induced expression of important thermogenic 134 genes including Ucp1, Cidea, Elovl3 and Pgc1α was repressed in sWAT of Rbp -/as 135 compared to WT mice (Fig. 3a) while Rbp deficiency had only modest or no effects on 136 thermogenic gene expression in BAT (Fig. 3b). Interestingly, circulating retinol and Rbp 137 correlated positively with Ucp1 expression in sWAT (Fig. 3c) and BAT (Fig. 3d), in keeping 138 with a functional relationship between vitamin A levels and the thermogenic program. A 139 hallmark of WAT browning is the emergence of cold-induced UCP1-positive multilocular 140 beige adipocytes. Whereas beige adipocytes were abundantly induced in sWAT of cold-141 exposed WT mice, adipocyte morphology as well as UCP1 protein expression in Rbp -/-sWAT 142 were not affected by cold exposure (Fig. 3e,g). Despite blunted sWAT browning, Rbp 143 deficiency did not interfere with the thermogenic program in BAT (Fig. 3b,f,h). Tissue 144 norepinephrine (NE) concentrations did not differ between cold-challenged WT and Rbp -/-145 mice (Fig. S1a) suggesting that altered sympathetic ...

Effects of Low Temperature on Antioxidant and Heat Shock Protein Expression Profiles and Transcriptomic Responses in Crayfish (Cherax destructor)

“…Retinol is involved in innate immunity and downregulates the expression of pro-inflammatory factors to exert anti-inflammatory effects [ 69 , 70 ]. In humans and rats, retinol has been found to have a regulatory effect at low temperatures [ 71 , 72 ]. In the present study, antibiotic biosynthesis and retinol metabolism were significantly changed in the low-temperature group.…”

Acute retinol mobilization by retinol-binding protein 4 in mouse liver induces fibroblast growth factor 21 expression

“…Thus, it appears that FGF21 triggers retinoid turnover/RAR activity specifically in the fat depot that undergoes browning. At this point, enhanced delivery of retinol via RBP4 to replenish tissue retinoids in thermogenic ingWAT but not pgWAT is rather speculative, but may be supported by the aforementioned report (58).…”

“…Physiologically, expression of Rbp4 in mouse liver is constitutively high and not known to be easily deflected in its dynamic, except by severe depletion of hepatic retinoid stores or a low biosynthetic capacity of the liver which downregulate expression and/or secretion of RBP4 (21). Intriguingly, and representing an exception to this general notion, cold exposure has been reported to increase the circulating concentrations of retinol and RBP4 in both mice and humans, coinciding with elevated expression of Rbp4 in mouse liver and being indicative for a coldinduced mobilization of hepatic retinoids (58). Impaired mobilization, due to RBP4 deficiency, led to defects in browning of subcutaneous WAT and adaptive thermogenesis in mice (58), suggesting that hepatic retinol mobilization is required for the adaptation to cold.…”

“…Intriguingly, and representing an exception to this general notion, cold exposure has been reported to increase the circulating concentrations of retinol and RBP4 in both mice and humans, coinciding with elevated expression of Rbp4 in mouse liver and being indicative for a coldinduced mobilization of hepatic retinoids (58). Impaired mobilization, due to RBP4 deficiency, led to defects in browning of subcutaneous WAT and adaptive thermogenesis in mice (58), suggesting that hepatic retinol mobilization is required for the adaptation to cold. Thus, cold exposure may represent a physiologic context for this model of acute mobilization of hepatic retinoids.…”