Retinol-binding protein 2 (RBP2) binds monoacylglycerols and modulates gut endocrine signaling and body weight

Abstract

Expressed in the small intestine, retinol-binding protein 2 (RBP2) facilitates dietary retinoid absorption. Rbp2-deficient (Rbp2−/−) mice fed a chow diet exhibit by 6-7 months-of-age higher body weights, impaired glucose metabolism, and greater hepatic triglyceride levels compared to controls. These phenotypes are also observed when young Rbp2−/− mice are fed a high fat diet. Retinoids do not account for the phenotypes. Rather, RBP2 is a previously unidentified monoacylglycerol (MAG)-binding protein, interacting with the endocannabinoid 2-arachidonoylglycerol (2-AG) and other MAGs with affinities comparable to retinol. X-ray crystallographic studies show that MAGs bind in the retinol binding pocket. When challenged with an oil gavage, Rbp2−/− mice show elevated mucosal levels of 2-MAGs. This is accompanied by significantly elevated blood levels of the gut hormone GIP (glucose-dependent insulinotropic polypeptide). Thus, RBP2, in addition to facilitating dietary retinoid absorption, modulates MAG metabolism and likely signaling, playing a heretofore unknown role in systemic energy balance.

Molecular basis for the interaction of cellular retinol binding protein 2 (CRBP2) with nonretinoid ligands

“…Rbp2 −/− mice maintained normal serum retinol levels. Also, there were no genotypedependent differences in all-trans-retinoic acid levels in the liver, white adipose tissue, or fasting and nonfasting intestinal tissue (9). These findings clearly indicate the previously unanticipated role of CRBP2 in energy homoeostasis on both the small intestinal and systemic levels.…”

“…Purification of human CRBP2 was performed essentially as described previously (9). The synthetic clone of cDNA (NP_004155.2; Origene Technologies) was inserted into pET3b vector (Novagen).…”

“…The phenotypic characterization of Rbp2 −/− mice established that this protein plays an essential role in facilitating the uptake and metabolism of ROL by enterocytes, particularly when the dietary availability of vitamin A is limited (8). Interestingly, the recent discovery of the interactions of CRBP2 with 2-arachidonoylglycerol (2-AG) and related MAGs added another dimension to the well-established retinoid-dependent physiological function of CRBP2 (9). It has been shown that in the absence of CRBP2, mice were more susceptible to developing obesity and metabolic disorders.…”

“…All CRBPs share the same protein structure architecture. These small soluble proteins fold into a single β-barrel that shields the central hydrophobic cavity that constitutes a solitary binding site for retinoids (9)(10)(11)(12). Access to the binding pocket is governed by a "portal region" composed of conformationally flexible loops connecting neighboring β-strands (Fig.…”

Analysis of exome-sequenced UK Biobank subjects implicates genes affecting risk of hyperlipidaemia

“…RBP2 (SLP=3.14) is expressed in the gut and its product is responsible for uptake of vitamin A but recent studies in mice have shown that it also influences body weight, the response to glucose challenge and hepatic triglyceride levels while Rbp2 deficient mice have increased adiposity, with larger adipocytes, and decreased energy expenditure (Lee et al, 2020). The authors suggest a signalling role for RBP2 and if similar mechanisms were present in humans then it is plausible that variants disrupting RBP2 could lead to increased risk of hyperlipidaemia.…”