CrbpI Modulates Glucose Homeostasis and Pancreas 9-cis-Retinoic Acid Concentrations

Abstract

Cellular retinol-binding protein type I (CrbpI), encoded by Rpb1, serves as a chaperone of retinol homeostasis, but its physiological effects remain incompletely understood. We show here that the Rbp1 ؊/؊ mouse has disrupted retinoid homeostasis in multiple tissues, with abnormally high 9-cis-retinoic acid (9cRA), a pancreas autacoid that attenuates glucose-stimulated insulin secretion. The Rbp1 ؊/؊ pancreas has increased retinol and intense ectopic expression of Rpb2 mRNA, which encodes CrbpII: both would contribute to increased ␤-cell 9cRA biosynthesis. 9cRA in Rbp1 ؊/؊ pancreas resists postprandial and glucose-induced decreases. Rbp1 (27,36). The relative amounts of apo-and holo-CrbpI facilitate cellular retinol uptake, modulate retinol storage as retinyl esters (RE), and affect retinoid homeostasis by regulating enzyme activity differentially (25, 34). Retinoic acid receptor (RAR) activation depends on CrbpI-mediated retinol uptake. CrbpI mutants with low retinol-binding affinity reduce RAR function in human mammary epithelial cells, leading to a loss of differentiation (10). Nevertheless, Rbp1 Ϫ/Ϫ mice are seemingly healthy and show no gross abnormalities characteristic of overt retinoid deficiency (13). All-trans-retinoic acid (atRA) in serum and several target tissues does not differ significantly between Rbp1 Ϫ/Ϫ and wild-type (WT) mice, likely accounting for lack of gross abnormalities (20, 29). Despite these insights, physiological effects of CrbpI remain to be elucidated fully.Retinol functions primarily through its metabolite atRA, which has diverse effects on energy metabolism. atRA induces pancreas development and differentiation into acini (18,24,28,32), but restricting dietary vitamin A in diabetes-prone rats reduces diabetes and insulitis, an effect not reversed by dosing atRA, suggesting contributions of additional retinoids (9). atRA arrests differentiation of preadipocytes into mature white adipocytes, early in the differentiation process (43, 48). Ablation of Rdh1, which encodes one of several short-chain dehydrogenases that catalyze the first and rate-limiting step in atRA biosynthesis from retinol, increases adiposity in mice fed a nonobesogenic diet (50). Dosing atRA ameliorates weight gain and represses insulin resistance in mice fed an obesogenic (high-fat) diet (3). atRA induces Ucp1, which encodes an uncoupling protein expressed in brown adipose tissue that supports thermogenesis (31).Although atRA mediates most vitamin A functions, 9-cis-RA (9cRA) occurs as an endogenous pancreas retinoid with unique actions independent of atRA (22). 9cRA, biosynthesized primarily by ␤-cells and detected only in pancreas, varies rapidly and inversely with serum glucose. 9cRA attenuates glucose-stimulated insulin secretion (GSIS): a decrease in 9cRA allows optimum glucose-stimulated insulin secretion, whereas dosing with 9cRA impairs insulin secretion and glucose tolerance. 9cRA acts, in part, through reduction of Glut2 and GK activities and through repressing expression of genes that function to pro...

Retinoids: Potent regulators of metabolism

“…A study of Rbp1 −/− mice, which lack CRBPI, by Kane et al confirmed the importance of CRBPI in glucose homeostasis (82). Rbp1 −/− mice fed a diet providing a relatively large amount of retinol (30 IU/g of diet) showed abnormally elevated pancreatic 9cRA levels and low insulin levels in the fed state, hyperglycemia, and marked glucose intolerance.…”

Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue

“…Retinoids, and the enzymes that control retinoid formation, represent a complex, highly regulated system that controls fundamental biological processes, including fuel metabolism 15,17,21 . We previously reported that mice lacking Aldh1a1 , the rate-limiting enzyme in Rald conversion to retinoic acid, show enhanced energy expenditure when fed a high-fat diet 16 , suggesting that they have altered BAT activity.…”

β-Carotene Supplementation Decreases Placental Transcription of LDL Receptor-Related Protein 1 in Wild-Type Mice and Stimulates Placental β-Carotene Uptake in Marginally Vitamin A-Deficient Mice

“…To be consistent with the nutritional requirements of the mice with an RBP knockout background, which represents the majority of the genetically modified strains in our colony, we fed our mice a diet containing vitamin A levels higher than those recommended (29). Other laboratories use a similar concentration of vitamin A in the mouse diet and define this diet as "copious in vitamin A" (30). Furthermore, note that the diet used in this study was different (same manufacturer, different product) from the diets used in previously published papers from our laboratory.…”