The Roles of Vitamin A in the Regulation of Carbohydrate, Lipid, and Protein Metabolism

Journal of Clinical Medicine - Tập 3 Số 2 - Trang 453-479
Wei Chen1, Guoxun Chen2
1Department of Nutrition, University of Tennessee at Knoxville, Knoxville, TN 37996, USA. [email protected].
2Department of Nutrition, University of Tennessee at Knoxville, Knoxville, TN 37996, USA. [email protected].

Tóm tắt

Currently, two-thirds of American adults are overweight or obese. This high prevalence of overweight/obesity negatively affects the health of the population, as obese individuals tend to develop several chronic diseases, such as type 2 diabetes and cardiovascular diseases. Due to obesity’s impact on health, medical costs, and longevity, the rise in the number of obese people has become a public health concern. Both genetic and environmental/dietary factors play a role in the development of metabolic diseases. Intuitively, it seems to be obvious to link over-nutrition to the development of obesity and other metabolic diseases. However, the underlying mechanisms are still unclear. Dietary nutrients not only provide energy derived from macronutrients, but also factors such as micronutrients with regulatory roles. How micronutrients, such as vitamin A (VA; retinol), regulate macronutrient homeostasis is still an ongoing research topic. As an essential micronutrient, VA plays a key role in the general health of an individual. This review summarizes recent research progress regarding VA’s role in carbohydrate, lipid, and protein metabolism. Due to the large amount of information regarding VA functions, this review focusses on metabolism in metabolic active organs and tissues. Additionally, some perspectives for future studies will be provided.

Từ khóa


Tài liệu tham khảo

WHO (2000). World Health Organization Technical Report Series, WHO.

WHO (2011). Global Status Report on Noncommunicable Diseases 2010—Description of the Global Burden of NCDs, Their Risk Factors and Determinants, World Health Organization.

Jensen, M.D., Ryan, D.H., Apovian, C.M., Loria, C.M., Ard, J.D., Millen, B.E., Comuzzie, A.G., Nonas, C.A., Donato, K.A., and Pi-Sunyer, F.X. (2013). 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J. Am. Coll. Cardiol.

Zhao, 2012, Roles of vitamin A status and retinoids in glucose and fatty acid metabolism, Biochem. Cell Biol., 90, 142, 10.1139/o11-079

Chen, 2013, Roles of Vitamin A Metabolism in the Development of Hepatic Insulin Resistance, ISRN Hepatol., 2013, 1, 10.1155/2013/534972

Fall, 2014, Genome-wide association studies of obesity and metabolic syndrome, Mol. Cell. Endocrinol., 382, 740, 10.1016/j.mce.2012.08.018

Kopelman, 2010, Symposium 1: Overnutrition: Consequences and solutions. Foresight Report: The obesity challenge ahead, Proc. Nutr. Soc., 69, 80, 10.1017/S0029665109991686

Key, 2010, Symposium 1: Overnutrition: Consequences and solutions. Obesity and cancer risk, Proc. Nutr. Soc., 69, 86, 10.1017/S0029665109991698

White, 2003, Insulin signaling in health and disease, Science, 302, 1710, 10.1126/science.1092952

Kasuga, 1982, Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor, Science, 215, 185, 10.1126/science.7031900

Petruzzelli, 1982, Insulin activates a tyrosine-specific protein kinase in extracts of 3T3-L1 adipocytes and human placenta, Proc. Natl. Acad. Sci. USA, 79, 6792, 10.1073/pnas.79.22.6792

McKern, 2006, Structure of the insulin receptor ectodomain reveals a folded-over conformation, Nature, 443, 218, 10.1038/nature05106

Cohen, 2006, The twentieth century struggle to decipher insulin signalling, Nat. Rev. Mol. Cell Biol., 7, 867, 10.1038/nrm2043

Taniguchi, 2006, Critical nodes in signalling pathways: Insights into insulin action, Nat. Rev. Mol. Cell Biol., 7, 85, 10.1038/nrm1837

Brown, 2008, Selective versus total insulin resistance: A pathogenic paradox, Cell Metab., 7, 95, 10.1016/j.cmet.2007.12.009

Johnson, 2013, The Origins and Drivers of Insulin Resistance, Cell, 152, 673, 10.1016/j.cell.2013.01.041

IARC (1999). IARC Handbooks of Cancer Prevention, IARC Scientific Publications.

Chambon, 1994, The retinoid signaling pathway: Molecular and genetic analyses, Semin. Cell Biol., 5, 115, 10.1006/scel.1994.1015

Lefebvre, 2005, Transcriptional activities of retinoic acid receptors, Vitam. Horm., 70, 199, 10.1016/S0083-6729(05)70007-8

Moore, 1930, Vitamin A and carotene: The absence of the liver oil vitamin A from carotene. VI. The conversion of carotene to vitamin A in vivo, Biochem. J., 24, 692, 10.1042/bj0240692

Moore, T. (1957). Vitamin A, Elsevier Publishing Company.

Rigtrup, 1992, A retinyl ester hydrolase activity intrinsic to the brush border membrane of rat small intestine, Biochemistry, 31, 2920, 10.1021/bi00126a011

Rigtrup, 1994, Purification and partial characterization of a retinyl ester hydrolase from the brush border of rat small intestine mucosa: Probable identity with brush border phospholipase B, Biochemistry, 33, 2661, 10.1021/bi00175a039

Erdman, 1993, Absorption and transport of carotenoids, Ann. N. Y. Acad. Sci., 691, 76, 10.1111/j.1749-6632.1993.tb26159.x

Parker, 1996, Absorption, metabolism, and transport of carotenoids, FASEB J., 10, 542, 10.1096/fasebj.10.5.8621054

Dew, 1994, Specificity of the retinol transporter of the rat small intestine brush border, Biochemistry, 33, 12340, 10.1021/bi00206a042

Goodman, 1965, Biosynthesis of vitamin A with rat intestinal enzymes, Science, 149, 879, 10.1126/science.149.3686.879

Wang, 1996, β-Oxidation in rabbit liver in vitro and in the perfused ferret liver contributes to retinoic acid biosynthesis from β-apocarotenoic acids, J. Biol. Chem., 271, 26490, 10.1074/jbc.271.43.26490

Kiefer, 2001, Identification and characterization of a mammalian enzyme catalyzing the asymmetric oxidative cleavage of provitamin A, J. Biol. Chem., 276, 14110, 10.1074/jbc.M011510200

Harrison, 2005, Mechanisms of digestion and absorption of dietary vitamin A, Annu. Rev. Nutr., 25, 87, 10.1146/annurev.nutr.25.050304.092614

MacDonald, 1988, Evidence for a lecithin-retinol acyltransferase activity in the rat small intestine, J. Biol. Chem., 263, 12478, 10.1016/S0021-9258(18)37779-2

Helgerud, 1982, Acyl CoA: Retinol acyltransferase in rat small intestine: Its activity and some properties of the enzymic reaction, J. Lipid Res., 23, 609, 10.1016/S0022-2275(20)38125-6

Ross, 2007, Retinol combined with retinoic acid increases retinol uptake and esterification in the lungs of young adult rats when delivered by the intramuscular as well as oral routes, J. Nutr., 137, 2371, 10.1093/jn/137.11.2371

Blomhoff, 1990, Transport and storage of vitamin A, Science, 250, 399, 10.1126/science.2218545

Kawaguchi, 2007, A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A, Science, 315, 820, 10.1126/science.1136244

Chassaing, 2009, Phenotypic spectrum of STRA6 mutations: From Matthew-Wood syndrome to non-lethal anophthalmia, Hum. Mutat., 30, E673, 10.1002/humu.21023

Golzio, 2007, Matthew-Wood syndrome is caused by truncating mutations in the retinol-binding protein receptor gene STRA6, Am. J. Hum. Genet., 80, 1179, 10.1086/518177

Berry, 2013, The STRA6 receptor is essential for retinol-binding protein-induced insulin resistance but not for maintaining vitamin A homeostasis in tissues other than the eye, J. Biol. Chem., 288, 24528, 10.1074/jbc.M113.484014

Ruiz, 2012, Retinoid content, visual responses, and ocular morphology are compromised in the retinas of mice lacking the retinol-binding protein receptor, STRA6, Investig. Ophthalmol. Vis. Sci., 53, 3027, 10.1167/iovs.11-8476

Terra, 2013, To investigate the necessity of STRA6 upregulation in T cells during T cell immune responses, PLoS One, 8, e82808, 10.1371/journal.pone.0082808

Napoli, 2012, Physiological insights into all-trans-retinoic acid biosynthesis, Biochim. Biophys. Acta, 1821, 152, 10.1016/j.bbalip.2011.05.004

Wolf, 2001, Retinoic acid homeostasis: Retinoic acid regulates liver retinol esterification as well as its own catabolic oxidation in liver, Nutr. Rev., 59, 391, 10.1111/j.1753-4887.2001.tb06968.x

Akawi, 1994, Rat liver cytosolic retinal dehydrogenase: Comparison of 13-cis-, 9-cis-, and all-trans-retinal as substrates and effects of cellular retinoid-binding proteins and retinoic acid on activity, Biochemistry, 33, 1938, 10.1021/bi00173a042

Matt, 2005, Retinoic acid-dependent eye morphogenesis is orchestrated by neural crest cells, Development, 132, 4789, 10.1242/dev.02031

Ziouzenkova, 2007, Retinaldehyde represses adipogenesis and diet-induced obesity, Nat. Med., 13, 695, 10.1038/nm1587

Reichert, 2011, Concerted action of aldehyde dehydrogenases influences depot-specific fat formation, Mol. Endocrinol., 25, 799, 10.1210/me.2010-0465

Zhai, 2001, Cellular expression of retinal dehydrogenase types 1 and 2: Effects of vitamin A status on testis mRNA, J. Cell. Physiol., 186, 220, 10.1002/1097-4652(200102)186:2<220::AID-JCP1018>3.0.CO;2-N

Lin, 2003, Mouse retinal dehydrogenase 4 (RALDH4), molecular cloning, cellular expression, and activity in 9-cis-retinoic acid biosynthesis in intact cells, J. Biol. Chem., 278, 9856, 10.1074/jbc.M211417200

Sima, 2009, Kinetic characterization of recombinant mouse retinal dehydrogenase types 3 and 4 for retinal substrates, Biochim. Biophys. Acta, 1790, 1660, 10.1016/j.bbagen.2009.09.004

Roberts, 1979, In vitro metabolism of retinoic acid in hamster intestine and liver, J. Biol. Chem., 254, 6296, 10.1016/S0021-9258(18)50362-8

Fujii, 1997, Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos, EMBO J., 16, 4163, 10.1093/emboj/16.14.4163

Wang, 2002, Cloning of rat cytochrome P450RAI (CYP26) cDNA and regulation of its gene expression by all-trans-retinoic acid in vivo, Arch. Biochem. Biophys., 401, 235, 10.1016/S0003-9861(02)00043-7

Ray, 1997, CYP26, a novel mammalian cytochrome P450, is induced by retinoic acid and defines a new family, J. Biol. Chem., 272, 18702, 10.1074/jbc.272.30.18702

Metzger, 2001, The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures, Genes Dev., 15, 226, 10.1101/gad.855001

Mangelsdorf, 1995, The nuclear receptor superfamily: The second decade, Cell, 83, 835, 10.1016/0092-8674(95)90199-X

Lehmann, 1991, Identification of retinoids with nuclear receptor subtype-selective activities, Cancer Res., 51, 4804

Berry, D.C., and Noy, N. (2007). Is PPAR β/δ a Retinoid Receptor?. PPAR Res., 2007.

Mayer, 1948, Influence of vitamin A deficiency on the gross efficiency of growth of rats, Yale J. Biol. Med., 20, 403

Sampson, 1932, The influence of vitamin A deficiency on male rats in paired feeding experiments, Biochem. J., 26, 1322, 10.1042/bj0261322

Zhang, 2012, Vitamin A status affects obesity development and hepatic expression of key genes for fuel metabolism in Zucker fatty rats, Biochem. Cell Biol., 90, 548, 10.1139/o2012-012

Rogers, 1969, Vitamin A deficiency in the rat prior to weaning, Proc. Soc. Exp. Biol. Med., 132, 622, 10.3181/00379727-132-34273

Anzano, 1979, Growth, appetite, sequence of pathological signs and survival following the induction of rapid, synchronous vitamin A deficiency in the rat, J. Nutr., 109, 1419, 10.1093/jn/109.8.1419

McCarthy, 1952, Vitamin A deficiency in the mouse, J. Nutr., 46, 361, 10.1093/jn/46.3.361

Sagazio, 2007, Vitamin A deficiency does not influence longitudinal growth in mice, Nutrition, 23, 483, 10.1016/j.nut.2007.04.004

Friedman, 1998, Leptin and the regulation of body weight in mammals, Nature, 395, 763, 10.1038/27376

Kumar, 1999, Dietary vitamin A supplementation in rats: Suppression of leptin and induction of UCP1 mRNA, J. Lipid Res., 40, 824, 10.1016/S0022-2275(20)32117-9

Hollung, 2004, Tissue-specific regulation of leptin expression and secretion by all-trans retinoic acid, J. Cell. Biochem., 92, 307, 10.1002/jcb.20047

Felipe, 2005, Effects of retinoic acid administration and dietary vitamin A supplementation on leptin expression in mice: Lack of correlation with changes of adipose tissue mass and food intake, Biochim. Biophys. Acta, 1740, 258, 10.1016/j.bbadis.2004.11.014

Bernard, 1968, Taste changes in vitamin A deficiency, J. Gen. Physiol., 52, 444, 10.1085/jgp.52.3.444

Reifen, 1998, Impaired responses to sweet taste in vitamin A-deficient rats, Metab. Clin. Exp., 47, 1, 10.1016/S0026-0495(98)90183-4

Russell, 1984, Impairment of taste and olfaction in patients with cirrhosis: The role of vitamin A, Hum. Nutr. Clin. Nutr., 38, 203

Moore, 1937, Vitamin A and carotene: The vitamin A reserve of the adult human being in health and disease, Biochem. J., 31, 155, 10.1042/bj0310155

Boeck, 1929, Xanthemia and xanthosis (carotinemia): Clinical study, J. Lab. Clin. Med., 14, 1129

Rabinowitch, 1930, Carotinemia and diabetes: II. The relationship between the sugar, cholesterol and carotin contents of blood plasma, Arch. Intern. Med., 45, 586, 10.1001/archinte.1930.00140100108010

Mosenthal, 1944, Vitamins A, B and C in diabetic children, Arch. Intern. Med., 73, 391, 10.1001/archinte.1944.00210170028004

Basu, 1989, Serum vitamin A and retinol-binding protein in patients with insulin-dependent diabetes mellitus, Am. J. Clin. Nutr., 50, 329, 10.1093/ajcn/50.2.329

Graham, 2006, Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects, N. Engl. J. Med., 354, 2552, 10.1056/NEJMoa054862

Cho, 2006, Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes, Diabetes Care, 29, 2457, 10.2337/dc06-0360

Wolf, 2007, Serum retinol-binding protein: A link between obesity, insulin resistance, and type 2 diabetes, Nutr. Rev., 65, 251, 10.1111/j.1753-4887.2007.tb00302.x

Craig, 2007, Retinol binding protein 4 as a candidate gene for type 2 diabetes and prediabetic intermediate traits, Mol. Genet. Metab., 90, 338, 10.1016/j.ymgme.2006.11.003

Kovacs, 2007, Effects of genetic variation in the human retinol binding protein-4 gene (RBP4) on insulin resistance and fat depot-specific mRNA expression, Diabetes, 56, 3095, 10.2337/db06-1647

Janke, 2006, Retinol-binding protein 4 in human obesity, Diabetes, 55, 2805, 10.2337/db06-0616

Ulgen, 2010, Association of serum levels of retinol-binding protein 4 with male sex but not with insulin resistance in obese patients, Arch. Physiol. Biochem., 116, 57, 10.3109/13813451003631421

Kotnik, 2011, RBP4: A controversial adipokine, Eur. J. Endocrinol., 165, 703, 10.1530/EJE-11-0431

Yang, 2005, Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes, Nature, 436, 356, 10.1038/nature03711

Motani, 2009, Identification and characterization of a non-retinoid ligand for retinol-binding protein 4 which lowers serum retinol-binding protein 4 levels in vivo, J. Biol. Chem., 284, 7673, 10.1074/jbc.M809654200

Bershad, 1985, Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne, N. Engl. J. Med., 313, 981, 10.1056/NEJM198510173131604

Tallman, 1992, Reassessing the hemostatic disorder associated with acute promyelocytic leukemia, Blood, 79, 543, 10.1182/blood.V79.3.543.543

Miller, 1994, Modulation of all-trans retinoic acid pharmacokinetics by liarozole, Cancer Chemother. Pharmacol., 34, 522, 10.1007/BF00685665

Gervois, 1998, Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids, J. Clin. Investig., 102, 625, 10.1172/JCI1581

Shachter, 2001, Apolipoproteins C-I and C-III as important modulators of lipoprotein metabolism, Curr. Opin. Lipidol., 12, 297, 10.1097/00041433-200106000-00009

Preitner, 2009, Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis, Am. J. Physiol. Endocrinol. Metab., 297, E1420, 10.1152/ajpendo.00362.2009

Mcilroy, 2013, Fenretinide treatment prevents diet-induced obesity in association with major alterations in retinoid homeostatic gene expression in adipose, liver, and hypothalamus, Diabetes, 62, 825, 10.2337/db12-0458

Wolf, 1957, Studies on the function of vitamin A in metabolism, J. Biol. Chem., 225, 995, 10.1016/S0021-9258(18)64896-3

Johnson, 1960, The function of vitamin A in carbohydrate metabolism. Its role in adrenocorticoid production, Vitam. Horm., 18, 457, 10.1016/S0083-6729(08)60875-4

Ray, A., and Sadhu, D.P. (1959). Carbohydrate metabolism in hypervitaminosis A. Nature, 184.

Singh, 1968, Early effects of feeding excess vitamin A: Hepatic glycogen, blood lactic acid, plasma NEFA and glucose tolerance in rats, Life Sci., 7, 239, 10.1016/0024-3205(68)90197-5

Singh, 1976, Early effects of excessive retinol intake on hepatic glycogen metabolism, Arch. Biochem. Biophys., 173, 93, 10.1016/0003-9861(76)90238-1

Shankar, 1990, The effect of the progression of vitamin A deficiency on glucose, galactose and mannose incorporation into sugar phosphates and sugar nucleotides in hamster liver, J. Nutr., 120, 361, 10.1093/jn/120.4.361

Singh, 1978, Early effects of vitamin A toxicity on hepatic glycolysis in rat, J. Nutr., 108, 1959, 10.1093/jn/108.12.1959

Chen, 2009, Retinoids synergize with insulin to induce hepatic Gck expression, Biochem. J., 419, 645, 10.1042/BJ20082368

Dileepan, 1981, Decreased hepatic gluconeogenesis in vitamin A-deficient rats, Proc. Soc. Exp. Biol. Med., 167, 248, 10.3181/00379727-167-41158

Singh, 1975, Role of adrenals in the vitamin A-mediated increase in the activities of gluconeogenic enzymes of rat liver, Life Sci., 17, 859, 10.1016/0024-3205(75)90436-1

Dileepan, 1977, Early effects of hypervitaminosis A on gluconeogenic activity and amino acid metabolizing enzymes of rat liver, J. Nutr., 107, 1809, 10.1093/jn/107.10.1809

Singh, 1976, Early effects of excessive retinol intake on gluconeogenesis. Involvement of adrenals in the increased activities on Gluconeogenic Enzymes of rat, Arch. Biochem. Biophys., 173, 82, 10.1016/0003-9861(76)90237-X

Zhang, 2011, Retinoids induced Pck1 expression and attenuated insulin-mediated suppression of its expression via activation of retinoic acid receptor in primary rat hepatocytes, Mol. Cell. Biochem., 355, 1, 10.1007/s11010-011-0831-4

Shin, 2002, Retinoid regulation of the phosphoenolpyruvate carboxykinase gene in liver, Mol. Cell. Endocrinol., 195, 39, 10.1016/S0303-7207(02)00215-0

Scribner, 2007, Nuclear receptor binding to the retinoic acid response elements of the phosphoenolpyruvate carboxykinase gene in vivo: Effects of vitamin A deficiency, J. Nutr. Biochem., 18, 206, 10.1016/j.jnutbio.2006.03.011

Sampson, 1932, The absorption of nitrogen and of fat from the alimentary canal of rats kept on a vitamin A-deficient diet, Biochem. J., 26, 1315, 10.1042/bj0261315

Brown, 1948, The effect of vitamin A deficiency upon the nitrogen metabolism of the rat, J. Nutr., 35, 425, 10.1093/jn/35.4.425

Cabezuelo, 2010, Vitamin A deficiency increases protein catabolism and induces urea cycle enzymes in rats, J. Nutr., 140, 792, 10.3945/jn.109.119388

John, 1989, Effect of vitamin A deficiency on nitrogen balance and hepatic urea cycle enzymes and intermediates in rats, J. Nutr., 119, 29, 10.1093/jn/119.1.29

Rao, 1966, Effect of vitamin A deficiency on the incorporation of 14C-Leucine into tissue proteins of rats, Nature, 210, 306, 10.1038/210306a0

Tryfiates, 1971, Effect of vitamin A deficiency on the protein synthetic activity of rat liver ribosomes, Proc. Soc. Exp. Biol. Med., 136, 946, 10.3181/00379727-136-35402

Nerurkar, 1956, Metabolism of calcium, phosphorus and nitrogen in hypervitaminosis A in young rats, Biochem. J., 63, 344, 10.1042/bj0630344

Gerber, 1982, Changes in lipid metabolism during retinoid administration, J. Am. Acad. Dermatol., 6, 664, 10.1016/S0190-9622(82)80047-9

Ellis, 1987, Glucose and insulin responses are improved in patients with psoriasis during therapy with etretinate, Arch. Dermatol., 123, 471, 10.1001/archderm.1987.01660280073026

Yehya, 2009, Hypervitaminosis A altering the lipid profile in a hypercholesterolemic patient, J. Clin. Lipidol., 3, 205, 10.1016/j.jacl.2009.03.001

Ellis, 1986, Increased risk for vitamin A toxicity in severe hypertriglyceridemia, Ann. Intern. Med., 105, 877, 10.7326/0003-4819-105-6-877

Lettinga, 1996, Early effects of high doses of retinol (vitamin A) on the in situ cellular metabolism in rat liver, Liver, 16, 1, 10.1111/j.1600-0676.1996.tb00696.x

Misra, 1965, Hypervitaminosis A and tissue fatty acids, Can. J. Biochem., 43, 1885, 10.1139/o65-207

Singh, 1969, Early effects of feeding excess vitamin A: Mechanism of fatty liver production in rats, J. Lipid Res., 10, 395, 10.1016/S0022-2275(20)43066-4

Ramachandran, 1975, Effect of excess and deficiency of vitamin A on the utilization of FFA by liver and skeletal muscle, Environ. Physiol. Biochem., 5, 208

Singh, 1978, Fatty liver in hypervitaminosis A: Synthesis and release of hepatic triglycerides, Am. J. Physiol., 234, E511

Oliveros, 2007, Vitamin A deficiency modifies lipid metabolism in rat liver, Br. J. Nutr., 97, 263, 10.1017/S0007114507182659

Khanna, 1983, Effect of undernutrition and vitamin A deficiency on the phospholipid composition of rat tissues at 21 days of age—I. Liver, spleen and kidney, Int. J. Vitam. Nutr. Res., 53, 3

Green, 1955, The effect of vitamin A deficiency on the cholesterol levels of the plasma and liver of the rat, Biochem. J., 61, 447, 10.1042/bj0610447

Wiss, 1980, Alterations of the lipid metabolism of rat liver as early symptoms of vitamin A deficiency, Int. J. Vitam. Nutr. Res., 50, 233

Green, 1934, Fat metabolism in vitamin A deficiency: The utilisation of fat and the desaturation of fat in the liver, Biochem. J., 28, 25, 10.1042/bj0280025

Kang, 2007, Altered lipid catabolism in the vitamin: A deficient liver, Mol. Cell. Endocrinol., 271, 18, 10.1016/j.mce.2007.03.002

Bonet, 2012, Lipid metabolism in mammalian tissues and its control by retinoic acid, Biochim. Biophys. Acta, 1821, 177, 10.1016/j.bbalip.2011.06.001

Horton, 2002, SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver, J. Clin. Investig., 109, 1125, 10.1172/JCI0215593

Chen, 2004, Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver, Proc. Natl. Acad. Sci. USA, 101, 11245, 10.1073/pnas.0404297101

Li, 2011, Retinoids synergized with insulin to induce Srebp-1c expression and activated its promoter via the two liver X receptor binding sites that mediate insulin action, Biochem. Biophys. Res. Commun., 406, 268, 10.1016/j.bbrc.2011.02.031

Deluca, 1963, Action of vitamin A on liver homogenate oxidation of tricarboxylic acid cycle intermediates, J. Nutr., 81, 383, 10.1093/jn/81.4.383

Seward, 1964, Respiratory activities of hypo- and hypervitaminotic A rat liver homogenates, Proc. Soc. Exp. Biol. Med., 117, 477, 10.3181/00379727-117-29612

Seward, 1966, Effect of vitamin A deficiency or excess on the oxidative phosphorylation by rat liver mitochondria, J. Biol. Chem., 241, 1229, 10.1016/S0021-9258(18)96824-9

Brissova, 2005, Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy, J. Histochem. Cytochem., 53, 1087, 10.1369/jhc.5C6684.2005

Andralojc, 2009, Ghrelin-producing epsilon cells in the developing and adult human pancreas, Diabetologia, 52, 486, 10.1007/s00125-008-1238-y

Unger, 2012, Glucagonocentric restructuring of diabetes: A pathophysiologic and therapeutic makeover, J. Clin. Investig., 122, 4, 10.1172/JCI60016

Gylfe, 2013, Glucose regulation of glucagon secretion, Diabetes Res. Clin. Pract., 103, 1, 10.1016/j.diabres.2013.11.019

Jensen, 2008, Metabolic cycling in control of glucose-stimulated insulin secretion, Am. J. Physiol. Endocrinol. Metab., 295, E1287, 10.1152/ajpendo.90604.2008

Chertow, 1994, Effects of vitamin A deficiency and repletion on rat glucagon secretion, Pancreas, 9, 475, 10.1097/00006676-199407000-00010

Chertow, 1996, Retinoic acid receptor transcripts and effects of retinol and retinoic acid on glucagon secretion from rat islets and glucagon-secreting cell lines, Metab. Clin. Exp., 45, 300, 10.1016/S0026-0495(96)90282-6

Matthews, 2004, Vitamin A deficiency impairs fetal islet development and causes subsequent glucose intolerance in adult rats, J. Nutr., 134, 1958, 10.1093/jn/134.8.1958

Chertow, 1987, Effects of vitamin A deficiency and repletion on rat insulin secretion in vivo and in vitro from isolated islets, J. Clin. Investig., 79, 163, 10.1172/JCI112778

Chertow, 1978, The effects of vitamin A on insulin release and glucose oxidation in isolated rat islets, Endocrinology, 103, 1562, 10.1210/endo-103-5-1562

Chertow, 1997, Effects of all-trans-retinoic acid (ATRA) and retinoic acid receptor (RAR) expression on secretion, growth, and apoptosis of insulin-secreting RINm5F cells, Pancreas, 15, 122, 10.1097/00006676-199708000-00003

Driscoll, 1997, Vitamin A stimulation of insulin secretion: Effects on transglutaminase mRNA and activity using rat islets and insulin-secreting cells, Pancreas, 15, 69, 10.1097/00006676-199707000-00010

German, 1999, Effect of retinoic acid on glucokinase activity and gene expression and on insulin secretion in primary cultures of pancreatic islets, Endocrinology, 140, 3091, 10.1210/endo.140.7.6765

Kane, 2010, Identification of 9-cis-retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion, Proc. Natl. Acad. Sci. USA, 107, 21884, 10.1073/pnas.1008859107

Kane, 2011, CrbpI modulates glucose homeostasis and pancreas 9-cis-retinoic acid concentrations, Mol. Cell. Biol., 31, 3277, 10.1128/MCB.05516-11

Ramachandran, 1986, Metabolic potential of the adipose tissue of rats during hyper- and hypovitaminosis A, Proc. Soc. Exp. Biol. Med., 182, 73, 10.3181/00379727-182-42311

Ribot, 2001, Changes of Adiposity in Response to Vitamin A Status Correlate with Changes of PPARγ2 Expression, Obesity, 9, 500, 10.1038/oby.2001.65

Ramalho, 2007, Association of serum concentrations of retinol and carotenoids with overweight in children and adolescents, Nutrition, 23, 392, 10.1016/j.nut.2007.02.009

Zulet, 2008, Vitamin A intake is inversely related with adiposity in healthy young adults, J. Nutr. Sci. Vitaminol., 54, 347, 10.3177/jnsv.54.347

Berry, 2009, All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor β/δ and retinoic acid receptor, Mol. Cell. Biol., 29, 3286, 10.1128/MCB.01742-08

Berry, 2012, Retinoic acid upregulates preadipocyte genes to block adipogenesis and suppress diet-induced obesity, Diabetes, 61, 1112, 10.2337/db11-1620

Mercader, 2006, Remodeling of white adipose tissue after retinoic acid administration in mice, Endocrinology, 147, 5325, 10.1210/en.2006-0760

Murholm, M., Isidor, M.S., Basse, A.L., Winther, S., Sørensen, C., Skovgaard-Petersen, J., Nielsen, M.M., Hansen, A.S., Quistorff, B., and Hansen, J.B. (2013). Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes. BMC Cell Biol., 14.

Schug, 2007, Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors, Cell, 129, 723, 10.1016/j.cell.2007.02.050

Shaw, 2003, Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptor β/δ, J. Biol. Chem., 278, 41589, 10.1074/jbc.C300368200

Kiefer, 2012, Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue, Nat. Med., 18, 918, 10.1038/nm.2757

Dimaculangan, 1994, Retinoic acid prevents downregulation of ras recision gene/lysyl oxidase early in adipocyte differentiation, Differentiation, 58, 47, 10.1046/j.1432-0436.1994.5810047.x

Berry, 2010, Repression of cellular retinoic acid-binding protein II during adipocyte differentiation, J. Biol. Chem., 285, 15324, 10.1074/jbc.M110.110635

Xue, 1996, Distinct stages in adipogenesis revealed by retinoid inhibition of differentiation after induction of PPARγ, Mol. Cell. Biol., 16, 1567, 10.1128/MCB.16.4.1567

Safonova, 1994, Retinoids are positive effectors of adipose cell differentiation, Mol. Cell. Endocrinol., 104, 201, 10.1016/0303-7207(94)90123-6

Cannon, 2004, Brown adipose tissue: Function and physiological significance, Physiol. Rev., 84, 277, 10.1152/physrev.00015.2003

Timmons, 2007, Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages, Proc. Natl. Acad. Sci. USA, 104, 4401, 10.1073/pnas.0610615104

Seale, 2007, Transcriptional control of brown fat determination by PRDM16, Cell Metab., 6, 38, 10.1016/j.cmet.2007.06.001

Wolf, 2009, Brown adipose tissue: The molecular mechanism of its formation, Nutr. Rev., 67, 167, 10.1111/j.1753-4887.2009.00184.x

Petrovic, 2010, Chronic peroxisome proliferator-activated receptor gamma (PPARγ) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes, J. Biol. Chem., 285, 7153, 10.1074/jbc.M109.053942

Wu, 2012, Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human, Cell, 150, 366, 10.1016/j.cell.2012.05.016

Cypess, 2013, Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat, Nat. Med., 19, 635, 10.1038/nm.3112

Lidell, 2013, Evidence for two types of brown adipose tissue in humans, Nat. Med., 19, 631, 10.1038/nm.3017

Nedergaard, 2013, How brown is brown fat? It depends where you look, Nat. Med., 19, 540, 10.1038/nm.3187

Bonet, 2000, Opposite effects of feeding a vitamin A-deficient diet and retinoic acid treatment on brown adipose tissue uncoupling protein 1 (UCP1), UCP2 and leptin expression, J. Endocrinol., 166, 511, 10.1677/joe.0.1660511

Puigserver, 1996, In vitro and in vivo induction of brown adipocyte uncoupling protein (thermogenin) by retinoic acid, Biochem. J., 317, 827, 10.1042/bj3170827

Alvarez, 1995, A novel regulatory pathway of brown fat thermogenesis. Retinoic acid is a transcriptional activator of the mitochondrial uncoupling protein gene, J. Biol. Chem., 270, 5666, 10.1074/jbc.270.10.5666

Larose, 1996, Essential cis-acting elements in rat uncoupling protein gene are in an enhancer containing a complex retinoic acid response domain, J. Biol. Chem., 271, 31533, 10.1074/jbc.271.49.31533

Ribot, 2004, Retinoic acid administration and vitamin A status modulate retinoid X receptor alpha and retinoic acid receptor alpha levels in mouse brown adipose tissue, Mol. Cell. Biochem., 266, 25, 10.1023/B:MCBI.0000049129.29612.14

Pedersen, 2011, Muscles and their myokines, J. Exp. Biol., 214, 337, 10.1242/jeb.048074

Sundeen, 1980, The effect of vitamin A deficiency on some postmortem parameters of avian muscle, Poult. Sci., 59, 2225, 10.3382/ps.0592225

Lee, 2008, Retinoic acid leads to cytoskeletal rearrangement through AMPK-Rac1 and stimulates glucose uptake through AMPK-p38 MAPK in skeletal muscle cells, J. Biol. Chem., 283, 33969, 10.1074/jbc.M804469200

Narbonne, 1978, Protein metabolism in vitamin A deficient rats. II. Protein synthesis in striated muscle, Ann. Nutr. Aliment, 32, 59

Hillgartner, 1982, Effect of excessive vitamin A intake on muscle protein turnover in the rat, Biochem. J., 202, 499, 10.1042/bj2020499

Amengual, 2008, Retinoic acid treatment increases lipid oxidation capacity in skeletal muscle of mice, Obesity, 16, 585, 10.1038/oby.2007.104