Background/Aims: Visceral fat (VF) compared with subcutaneous fat (SF) is more closely associated with cardiometabolic disease. Dietary vitamin A (retinol) may reduce adiposity through its effects on adipogenesis differentially in VF and SF, and this effect may be modulated by retinol-binding protein-4 (RBP4). We investigated whether intake of vitamin A is associated with either VF or SF, and whether this association is moderated by the RBP4 genotype (rs10882272, C/T) previously associated with circulating retinol levels. Methods: This was a cross-sectional association study in a sample of 947 adolescents from a French-Canadian founder population. VF and SF were quantified with magnetic resonance imaging, and vitamin A intake was assessed with a 24-hour food recall. All participants were genotyped to determine their RBP4 variant. Results: Dietary intake of vitamin A was negatively associated with VF; however, it was not associated with SF. These relationships were independent of age, sex, height and energy intake, and were modulated by the RBP4 variant. The T allele promoted adiposity-reducing effects of vitamin A in VF and adiposity-enhancing effects in SF, while the C allele had adiposity-reducing effects in both VF and SF. Conclusions: Dietary vitamin A may reduce abdominal adiposity and promote visceral to subcutaneous body fat redistribution during adolescence in an RBP4-dependent manner. These observational findings provide the basis for future interventional studies, which together with genetic information may inject further causality in the association between dietary vitamin A intake and abdominal adiposity.

Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH: The disease burden associated with overweight and obesity. JAMA 1999;282:1523-1529.
Cornier MA, Despres JP, Davis N, Grossniklaus DA, Klein S, Lamarche B, Lopez-Jimenez F, Rao G, St-Onge MP, Towfighi A, Poirier P: Assessing adiposity: a scientific statement from the American Heart Association. Circulation 2011;124:1996-2019.
Thorne A, Lonnqvist F, Apelman J, Hellers G, Arner P: A pilot study of long-term effects of a novel obesity treatment: omentectomy in connection with adjustable gastric banding. Int J Obes Relat Metab Disord 2002;26:193-199.
Taksali SE, Caprio S, Dziura J, Dufour S, Cali AM, Goodman TR, Papademetris X, Burgert TS, Pierpont BM, Savoye M, Shaw M, Seyal AA, Weiss R: High visceral and low abdominal subcutaneous fat stores in the obese adolescent: a determinant of an adverse metabolic phenotype. Diabetes 2008;57:367-371.
Pou KM, Massaro JM, Hoffmann U, Lieb K, Vasan RS, O'Donnell CJ, Fox CS: Patterns of abdominal fat distribution: the Framingham Heart Study. Diabetes Care 2009;32:481-485.
Porter SA, Massaro JM, Hoffmann U, Vasan RS, O'Donnel CJ, Fox CS: Abdominal subcutaneous adipose tissue: a protective fat depot? Diabetes Care 2009;32:1068-1075.
Dencker M, Wollmer P, Karlsson MK, Linden C, Andersen LB, Thorsson O: Body fat, abdominal fat and body fat distribution related to cardiovascular risk factors in prepubertal children. Acta Paediatr 2012;101:852-857.
Tran TT, Yamamoto Y, Gesta S, Kahn CR: Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab 2008;7:410-420.
Klein S, Fontana L, Young VL, Coggan AR, Kilo C, Patterson BW, Mohammed BS: Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N Engl J Med 2004;350:2549-2557.
Demerath EW, Reed D, Rogers N, Sun SS, Lee M, Choh AC, Couch W, Czerwinski SA, Chumlea WC, Siervogel RM, Towne B: Visceral adiposity and its anatomical distribution as predictors of the metabolic syndrome and cardiometabolic risk factor levels. Am J Clin Nutr 2008;88:1263-1271.
Alligier M, Gabert L, Meugnier E, Lambert-Porcheron S, Chanseaume E, Pilleul F, Debard C, Sauvinet V, Morio B, Vidal-Puig A, Vidal H, Laville M: Visceral fat accumulation during lipid overfeeding is related to subcutaneous adipose tissue characteristics in healthy men. J Clin Endocrinol Metab 2013;98:802-810.
McLaughlin T, Lamendola C, Liu A, Abbasi F: Preferential fat deposition in subcutaneous versus visceral depots is associated with insulin sensitivity. J Clin Endocrinol Metab 2011;96:E1756-E1760.
Yasmeen R, Jeyakumar SM, Reichert B, Yang F, Ziouzenkova O: The contribution of vitamin A to autocrine regulation of fat depots. Biochim Biophys Acta 2012;1821:190-197.
Harrison EH: Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A carotenoids. Biochim Biophys Acta 2012;1821:70-77.
Shirakami Y, Lee SA, Clugston RD, Blaner WS: Hepatic metabolism of retinoids and disease associations. Biochim Biophys Acta 2012;1821:124-136.
Goodman DS: Plasma retinol-binding protein. Ann NY Acad Sci 1980;348:378-390.
Gamble MV, Ramakrishnan R, Palafox NA, Briand K, Berglund L, Blaner WS: Retinol binding protein as a surrogate measure for serum retinol: studies in vitamin A-deficient children from the republic of the Marshall islands. Am J Clin Nutr 2001;73:594-601.
de Pee S, Dary O: Biochemical indicators of vitamin A deficiency: serum retinol and serum retinol binding protein. J Nutr 2002;132:2895S-2901S.
Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P, Wiita P, Bok D, Sun H: A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science 2007;315:820-825.
Shao D, Lazar MA: Peroxisome proliferator activated receptor gamma, CCAAT/enhancer-binding protein alpha, and cell cycle status regulate the commitment to adipocyte differentiation. J Biol Chem 1997;272:21473-21478.
Bonet ML, Ribot J, Palou A: Lipid metabolism in mammalian tissues and its control by retinoic acid. Biochim Biophys Acta 2012;1821:177-189.
Ziouzenkova O, Orasanu G, Sharlach M, Akiyama TE, Berger JP, Viereck J, Hamilton JA, Tang G, Dolnikowski GG, Vogel S, Duester G, Plutzky J: Retinaldehyde represses adipogenesis and diet-induced obesity. Nat Med 2007;13:695-702.
Berry DC, Jin H, Majumdar A, Noy N: Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses. Proc Natl Acad Sci USA 2011;108:4340-4345.
Ribot J, Felipe F, Bonet ML, Palou A: Changes of adiposity in response to vitamin A status correlate with changes of PPAR gamma 2 expression. Obes Res 2001;9:500-509.
Redonnet A, Ferrand C, Bairras C, Higueret P, Noel-Suberville C, Cassand P, Atgie C: Synergic effect of vitamin A and high-fat diet in adipose tissue development and nuclear receptor expression in young rats. Br J Nutr 2008;100:722-730.
Kloting N, Graham TE, Berndt J, Kralisch S, Kovacs P, Wason CJ, Fasshauer M, Schon MR, Stumvoll M, Bluher M, Kahn BB: Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab 2007;6:79-87.
Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB: Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 2005;436:356-362.
Moraes-Vieira PM, Yore MM, Dwyer PM, Syed I, Aryal P, Kahn BB: RBP4 activates antigen-presenting cells, leading to adipose tissue inflammation and systemic insulin resistance. Cell Metab 2014;19:512-526.
Farjo KM, Farjo RA, Halsey S, Moiseyev G, Ma JX: Retinol-binding protein 4 induces inflammation in human endothelial cells by an NADPH oxidase- and nuclear factor kappa B-dependent and retinol-independent mechanism. Mol Cell Biol 2012;32:5103-5115.
Norseen J, Hosooka T, Hammarstedt A, Yore MM, Kant S, Aryal P, Kiernan UA, Phillips DA, Maruyama H, Kraus BJ, Usheva A, Davis RJ, Smith U, Kahn BB: Retinol-binding protein 4 inhibits insulin signaling in adipocytes by inducing proinflammatory cytokines in macrophages through a c-Jun N-terminal kinase- and toll-like receptor 4-dependent and retinol-independent mechanism. Mol Cell Biol 2012;32:2010-2019.
Mondul AM, Yu K, Wheeler W, Zhang H, Weinstein SJ, Major JM, Cornelis MC, Mannisto S, Hazra A, Hsing AW, Jacobs KB, Eliassen H, Tanaka T, Reding DJ, Hendrickson S, Ferrucci L, Virtamo J, Hunter DJ, Chanock SJ, Kraft P, Albanes D: Genome-wide association study of circulating retinol levels. Hum Mol Genet 2011;20:4724-4731.
Pausova Z, Paus T, Abrahamowicz M, Almerigi J, Arbour N, Bernard M, Gaudet D, Hanzalek P, Hamet P, Evans AC, Kramer M, Laberge L, Leal SM, Leonard G, Lerner J, Lerner RM, Mathieu J, Perron M, Pike B, Pitiot A, Richer L, Seguin JR, Syme C, Toro R, Tremblay RE, Veillette S, Watkins K: Genes, maternal smoking, and the offspring brain and body during adolescence: design of the Saguenay Youth study. Hum Brain Mapp 2007;28:502-518.
Thompson FE, Subar AF: Dietary assessment methodology; in Bousky C (ed): Nutrition in the Prevention and Treatment of Disease. San Diego, Academic Press, 2008.
Buzzard IM, Faucett CL, Jeffery RW, McBane L, McGovern P, Baxter JS, Shapiro AC, Blackburn GL, Chlebowski RT, Elashoff RM, Wynder EL: Monitoring dietary change in a low-fat diet intervention study: advantages of using 24-hour dietary recalls vs food records. J Am Diet Assoc 1996;96:574-579.
Berthiaume P, Lavalee C, Villeneuve M, Vigneaut M: Enquête sociale et de santé auprès des enfants et des adolescents québécois. Volet nutrition. Quebec, Les Publications du Québec, 2004, pp 19-33.
Davey Smith G, Hemani G: Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 2014;23:R89-R98.
Sauma L, Franck N, Paulsson JF, Westermark GT, Kjolhede P, Stralfors P, Soderstrom M, Nystrom FH: Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes. Diabetologia 2007;50:195-201.
Muenzner M, Tuvia N, Deutschmann C, Witte N, Tolkachov A, Valai A, Henze A, Sander LE, Raila J, Schupp M: Retinol-binding protein 4 and its membrane receptor STRA6 control adipogenesis by regulating cellular retinoid homeostasis and retinoic acid receptor alpha activity. Mol Cell Biol 2013;33:4068-4082.
Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Naslund E, Britton T, Concha H, Hassan M, Ryden M, Frisen J, Arner P: Dynamics of fat cell turnover in humans. Nature 2008;453:783-787.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.