Liver-secreted RBP4 does not impair glucose homeostasis in mice

Fedders, Ronja; Muenzner, Matthias; Weber, Pamela; Sommerfeld, Manuela; Knauer, Miriam; Kedziora, Sarah; Kast, Naomi; Heidenreich, Steffi; Raila, Jens; Weger, Stefan; Henze, Andrea; Schupp, Michael

doi:10.1074/jbc.ra118.004294

Cited by 36 publications

(45 citation statements)

References 33 publications

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“…However, a recent study indicated that both mRNA and protein levels of RBP4 are increased in liver of humans with nonalcoholic fatty liver disease and RBP4 mRNA expression correlates with hepatic triglyceride content . Adeno‐associated viral overexpression of RBP4 in liver does not impair whole body glucose tolerance in mice but serum RBP4 levels were not elevated in that study and hepatic insulin sensitivity was not assessed . Finally, adipocyte‐selective overexpression of RBP4 and global overexpression of RBP4 both result in glucose intolerance and increased hepatic lipid accumulation even on a chow diet …”

Section: Discussionmentioning

confidence: 80%

RBP4 increases lipolysis in human adipocytes and is associated with increased lipolysis and hepatic insulin resistance in obese women

et al. 2020

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This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractRetinol-binding protein-4 (RBP4) is elevated in serum and adipose tissue (AT) in obesity-induced insulin resistance and correlates inversely with insulin-stimulated glucose disposal. But its role in insulin-mediated suppression of lipolysis, free fatty acids (FFA), and endogenous glucose production (EGP) in humans is unknown. RBP4 mRNA or protein levels were higher in liver, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in morbidly obese subjects undergoing Roux-en-Y gastric bypass surgery compared to lean controls undergoing elective laparoscopic cholecystectomy. RBP4 mRNA expression in SAT correlated with the expression of several macrophage and other inflammation markers. Serum RBP4 levels correlated inversely with glucose disposal and insulin-mediated suppression of lipolysis, FFA, and EGP. Mechanistically, RBP4 treatment of human adipocytes in vitro directly stimulated basal lipolysis. Treatment of adipocytes with conditioned media from RBP4-activated macrophages markedly increased basal lipolysis and impaired insulin-mediated lipolysis suppression. RBP4 treatment of macrophages increasedTNFα production. These data suggest that elevated serum or adipose tissue RBP4 levels in morbidly obese subjects may cause hepatic and systemic insulin resistance by stimulating basal lipolysis and by activating macrophages in adipose tissue, resulting in release of pro-inflammatory cytokines that impair lipolysis suppression. While we have demonstrated this mechanism in human adipocytes in vitro, and correlations from our flux studies in humans strongly support this, further studies are needed 6100 |

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Section: Discussionmentioning

confidence: 80%

RBP4 increases lipolysis in human adipocytes and is associated with increased lipolysis and hepatic insulin resistance in obese women

et al. 2020

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“…Primary hepatocyte isolation and cell culture Hepatocytes were isolated as described previously (53). In short, livers of anesthetized male wt mice or male mice with floxed Egln3 alleles (45) were perfused with digestion buffer containing 5000 U collagenase (Worthington).…”

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confidence: 99%

The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation

Heidenreich

Weber

Stephanowitz

et al. 2020

Journal of Biological Chemistry

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Cellular energy demands are met by uptake and metabolism of nutrients like glucose. The principal transcriptional regulator for adapting glycolytic flux and downstream pathways like de novo lipogenesis to glucose availability in many cell types is carbohydrate response element binding protein (ChREBP). ChREBP is activated by glucose metabolites and post-translational modifications, inducing nuclear accumulation and regulation of target genes. Here we report that ChREBP is modified by proline hydroxylation at several residues. Proline hydroxylation targets both ectopically expressed ChREBP in cells and endogenous ChREBP in mouse liver. Functionally, we found that specific hydroxylated prolines were dispensable for protein stability but required for the adequate activation of ChREBP upon exposure to high glucose. Accordingly, ChREBP target gene expression was rescued by re-expressing wild-type but not ChREBP that lacks hydroxylated prolines in ChREBP-deleted hepatocytes. Thus, proline hydroxylation of ChREBP is a novel post-translational modification that may allow for therapeutic interference in metabolic diseases.

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“…Mice with hepatocyte-specific deletion of Rbp (LRKO) exhibit no detectable plasma Rbp levels on chow or high-fat diet despite intact adipose Rbp production, establishing hepatocytes as the principal source of circulating Rbp. More importantly, LRKO mice are not protected from diet-induced obesity or insulin resistance consistent with adipocyte-secreted Rbp is confined to autocrine or paracrine actions within adipose tissue, even in an insulin resistant state (Fedders et al, 2018; Thompson et al, 2017). In support of this notion, adipocyte-specific Rbp overexpression increases adipose tissue inflammation, lipolysis and circulating FA levels (Lee, Yuen, Jiang, Kahn, & Blaner, 2016).…”

Section: Discussionmentioning

confidence: 94%

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

Fenzl

Kulterer

Spirk

et al. 2020

Preprint

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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 ...

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Liver-secreted RBP4 does not impair glucose homeostasis in mice

Cited by 36 publications

References 33 publications

RBP4 increases lipolysis in human adipocytes and is associated with increased lipolysis and hepatic insulin resistance in obese women

RBP4 increases lipolysis in human adipocytes and is associated with increased lipolysis and hepatic insulin resistance in obese women

The glucose-sensing transcription factor ChREBP is targeted by proline hydroxylation

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

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