β-Carotene conversion products and their effects on adipose tissue
© Springer-Verlag 2009
Received: 22 May 2009
Accepted: 27 May 2009
Published: 26 June 2009
Recent epidemiological data suggest that β-carotene may be protective against metabolic diseases in which adipose tissue plays a key role. Adipose tissue constitutes the major β-carotene storage tissue and its functions have been shown to be modulated in response to β-carotene breakdown products, especially retinal produced after cleavage by β-carotene 15,15′-monooxygenase (BCMO1), and retinoic acid arising from oxidation of retinal. However, the possibility exists that β-carotene in its intact form can also affect adipocyte function. Development of a knock out model and identification of a loss-of-function mutation have pointed out BCMO1 as being probably the sole enzyme responsible for provitamin A conversion into retinal in mammals. The utilisation of BCMO1−/−mice should provide insights on β-carotene effect on its own in the future. In humans, intervention studies have highlighted the huge interindividual variation of β-carotene conversion efficiency, possibly due to genetic polymorphisms, which might impact on response to β-carotene. This brief review discusses the processes involved in β-carotene conversion and the effect of cleavage products on body fat and adipose tissue function.
Carotenoids and provitamin A
Carotenoids are C40 lipophilic pigments produced by photosynthetic organisms. About 600 different compounds have been identified so far, of which 50 can be found in the human diet. However, only about 10 are present in significant amounts in human plasma . Carotenoids can be divided into two groups according to their chemical structure: the carotenes, which are hydrocarbons, and the xanthophylls, which contain also oxygen and are therefore more polar than the carotenes. The difference in polarity has consequences on their tissue distribution and also influences repartition and exchange between lipoproteins [46, 70]. Carotenoids containing an unsubstituted β-ring and a C11 polyene chain are termed provitamin A as they can be cleaved by animals to release retinal, which can be subsequently converted to retinol (vitamin A, see below). β-Carotene constitutes the main provitamin A source with a daily consumption of around 1–3 mg [23, 24, 27, 64].
A high dietary consumption or a high plasma carotenoid status has generally been associated with a decreased risk of chronic disease (such as cardiovascular disease, some types of cancer and ocular diseases) in observational studies [2, 40]. Furthermore, several studies have found a lower β-carotene status in patients suffering from type II diabetes or metabolic syndrome than in matched controls [10, 19, 20, 55, 56, 65, 82]. Oxidative stress has been implicated in the triggering and/or the perpetuation of chronic and metabolic diseases, and the hypothesis was developed that increased intake of antioxidants (carotenoids, polyphenols, tocopherols) would prevent oxidative stress and disease occurrence. Until recently, beneficial health effects attributed to carotenoids were associated with their capability of acting as “direct” antioxidants (e.g. as free radical scavengers) in lipophilic environments such as biomembranes and lipoproteins . However, current research is investigating the possibility that the beneficial health effects of phytochemicals could be caused by modulation of gene expression and induced endogenous defence mechanisms .
Interestingly, several intervention trials have failed in showing any preventive effects of carotenoids on disease incidence, and in some cases long-term supra-physiological dosing has even proven to be harmful in people at risk of disease [5, 21]. These data suggest the existence of a window of benefit for β-carotene and that an optimal carotenoid status should be achieved via appropriate food intake to avoid disease development. Furthermore, this window of benefit might vary between individuals, depending on their lifestyle and genetic background, both being susceptible of modulating response to carotenoids, as discussed below. Human adipose tissue represents the main β-carotene store of the body  and has a key role in metabolic pathologies . Therefore, it could be conceivable that a putative β-carotene effect would also occur in or be mediated by the adipose tissue. However, the underlying effects of β-carotene on health are still unclear and could involve antioxidant properties but also modulation of gene expression and/or cell communication by β-carotene and/or its derivatives .
At the intestinal level, β-carotene absorption is depending on three steps: (1) absorption at the enterocyte brush border membrane level, partly via the cholesterol transporters SR-BI and CD36 [11, 71] but also by passive diffusion ; (2) enzymatic conversion of a fraction of absorbed β-carotene in a centric or eccentric fashion by the β-carotene 15,15′-monooxygenase BCMO1 (releasing retinal) or by the β-carotene 9′,10′-dioxygenase, BCDO2 (releasing β-apo-10′-carotenal and β-ionone), respectively (Fig. 2, for review see . Because production of other β-apocarotenals (8′, 12′ and 14′) has also been reported, the existence of an additional enzymatic eccentric pathway (similar to fatty acid β-oxidation) has been proposed [26, 76], although production of such compounds could also occur by non enzymatic oxidation [80, 81]. Furthermore, the extent of β-carotene cleavage in enterocytes is species-dependent: humans (and other species such as ferrets) but not rodents, absorb significant amounts of intact β-carotene . Retinal is subsequently metabolised into retinol by retinal dehydrogenases (RDHs), followed by esterification to fatty acids by lecithin:retinol acyl transferase (LRAT) and acyl-CoA:retinol acyltransferase (ARAT) . Retinyl esters are then packed into chylomicrons together with non-converted β-carotene . A minor fraction of retinal is also oxidised irreversibly to retinoic acids (RAs) via the retinal dehydrogenases (RALDHs). The fate of apocarotenals has not been described in detail but a part of them is probably oxidised to the corresponding apocarotenoic acid. And finally, (3) the secretion of chylomicron into the lymph. More hydrophilic compounds such as non-esterified retinol and RA are secreted directly into the bloodstream .
SNPs related to β-carotene status/metabolism
Effect of the minor allele
Decreased fasting β-carotene in men
Exon 5 T170 M
High plasma β-carotene
Decreased catalytic activity in vitro
Exon 8 (R267S) or
Decreased intestinal postprandial β-carotene conversion efficiency, higher fasting β-carotene
Exon 6 + exon 8 (R267S + A379 V)
Higher β-carotene concentrations in homozygous women
Exon 8 S447X
Lower fasting plasma β-carotene
Decreased fasting β-carotene in men
The β-carotene 15,15′-monooxygenase knock out model
Carotenoid/retinoid pathway and lipid metabolism
Vitamin A status seems to play an important role in the development of liver steatosis in mice. A decrease in the expression of genes involved in fatty acid oxidation and an increase in hepatic macrocytic lipid accumulation and triglyceride concentration  have been observed in the liver of vitamin A deficient mice. Besides, the importance of RA was demonstrated in transgenic mice expressing retinoic acid receptor α dominant negative form (RARE) who develop microvesicular steatosis and spotty focal necrosis. Feeding these mice on a high retinoic acid diet reversed histological and biochemical abnormalities . Surprisingly, BCMO1 −/− mice were also found to develop liver steatosis . However, it is important to note that in the case of BCMO1 −/− mice, liver stores of WT and KO animals after feeding a vitamin A sufficient diet were comparable , suggesting that the development of steatosis in this animal model is directly related to BCMO1 function and not to vitamin A status. Therefore, it is possible that the local synthesis of vitamin A isomers from β-carotene could be mandatory for some physiological processes, such as described for zebrafish normal embryogenesis . Other observations that support the existence of a relationship between carotenoid/retinoid and lipid metabolism come from studies investigating the effect of retinoids on body fat content. Bovine marbling (which is the presence of a high amount of fat in muscle) is enhanced in the cattle by diets low in carotenoids, so that marbling development is inversely correlated with serum vitamin A levels . In rodents, the administration of RA (reviewed in ) or retinal  reduces body weight and body fat, and increases insulin sensitivity. Long-term vitamin A supplementation (as retinyl palmitate) has been shown to associate with a mild reduction of adiposity in rats  and has certain counterbalancing effect on the development of diet-induced obesity in mice . On the other hand, feeding mice with a vitamin A deficient diet results in a marked increase in adiposity . Of note, there are studies linking a low dietary intake of vitamin A with a high incidence of obesity in certain human populations [72, 78]. Even if, in rodents, increases in skeletal muscle fatty acid oxidation  and changes in liver metabolism (Amengual et al., unpublished results) can contribute to the RA slimming effect, there is strong evidence that the major role of carotenoid derivatives is on adipose tissue (see next section).
Effect of β-carotene and its metabolites on adipose tissue biology
Adipose tissue is primarily a lipid storage organ. To perform this function it is in active communication with other organs, receiving and sending signals . Alterations in the secretion of these molecules, and also in the ability of adipose tissue to expand appropriately under conditions of positive energy balance, have been shown to influence the aetiology of several pathologies including type II diabetes and cardiovascular diseases. Interestingly, the adipose tissue, and adipocytes in particular, are also the main β-carotene storage sites in humans . Therefore, it is particularly relevant to study the effect of β-carotene on this organ, especially in relation to adipocyte differentiation, adipokine secretion, and lipid metabolism, which are crucial aspects of adipose tissue biology. Since BCMO1 and BCDO2 are expressed in adipocytes , the possibility exists that the cleavage products could be found in adipocytes. In fact, retinal, which can be produced via BCMO1 cleavage, has been detected in adipose tissue . RAs resulting from oxidation of retinal by RALDHs are also quantifiable in adipose tissue in vivo , especially all-trans RA; whereas evidence of the existence of 9-cis RA in vivo is still lacking [35, 52, 68]. Finally, apocarotenals resulting from asymmetric cleavage of β-carotene can be generated in vivo  and may influence parameters of adipose tissue biology, even if no data are currently available on the presence of these molecules in adipocytes.
Adipose tissue is highly plastic. It has an enormous capacity to expand through hypertrophy and hyperplasia of adipocytes. Preadipocytes can differentiate to adipocytes. This differentiation is triggered by nutritional and hormonal signals that activate a cascade of transcription factors including the CCAAT/enhancer binding proteins (C/EBPs) and peroxisome proliferator-activated receptor γ (PPARγ), the latter being considered as the master regulator of adipogenesis (for review see ).
The effect of β-carotene has been depicted on the differentiation of 3T3-L1 preadipocytes, the prototypical model for such studies . Results showed that β-carotene strongly inhibited adipose conversion of 3T3-L1 cells. However, based on these results, one cannot exclude a vitamin A rather than a β-carotene effect. Indeed, it is well known that vitamin A derivatives are strong repressors of adipocyte differentiation. This was established long ago for RA , and a recent article elegantly demonstrated that physiological concentration of retinal represses adipogenesis in vitro and in vivo  through inhibition of RXRα (retinoid X receptor α) and PPARγ-activation by their respective ligands (Fig. 2). The same group has also shown that the asymmetric cleavage product β-apo-14′-carotenal (but not β-apo-8′carotenal and β-apo-12′-carotenal) presents inhibitory properties on preadipocyte differentiation via suppression of PPARα, PPARγ and RXR-activation by their respective ligands .
RA has been largely studied as a modulator of mammalian gene expression. Main effects are mediated by two types of nuclear hormone receptors: the retinoid X receptors (RXRα, RXRβ and RXRγ), which are responsive to 9-cis RA and the retinoic acid receptors (RARα, RARβ and RARγ), responsive to all-trans and 9-cis RA. These nuclear receptors have very broad repercussions on general homeostasis. RXRs act as partners to other class II nuclear receptors, including thyroid hormone receptor, vitamin D receptor, PPAR, farnesoid X receptor and the liver X receptor, leading to multiple biological effects . Similarly, RARs with RXRs as heterodimerisation partners have biological effects ranging from morphogenesis and organogenesis, to cell growth, differentiation and apoptosis .
In the specific context of adipocyte differentiation, the effect of all-trans RA has been related to several events (reviewed in ). Among them, RAs interfered with C/EBP proteins, which resulted in a blockage of induction of downstream target genes, including PPARγ. An effect on RARγ (up-regulation) and RXRα (down-regulation) expression has been demonstrated, which modifies the assembly of nuclear receptors heterodimers involved in adipogenesis. Finally, effects of RAs on the retinoblastoma protein may favour the proliferative ability, and thus reduce the differentiation ability of preadipocytes. Interestingly, low concentrations (1–10 nM) of RAs, contrary to high concentrations (0.1–1 μM), appear to have a stimulating effect on adipogenesis (reviewed in ).
Finally, it should also be taken into account that both in vivo and in vitro RA (all-trans and 9-cis) has been shown to induce the expression of uncoupling protein-1 (UCP1), the molecular marker of brown adipocytes. Provitamin A carotenoids also induced UCP1 expression in primary brown adipocytes differentiated in culture . This induction is explained by the existence of RA and PPAR response elements in the UCP1 gene promoter. Induction of other UCP family members by all-trans RA has also been reported (see ).
Adipokines are bioactive proteins secreted by the adipose tissue that act locally or at a distance to affect adipose tissue growth and whole body metabolism. More than 50 different adipokines have been identified so far, including: adiponectin, leptin, resistin, acylation stimulating protein, fasting-induced adipose factor, enzymes involved in lipoprotein metabolism and various cytokines, chemokines and acute phase proteins [59, 62, 69, 74]. In 2005, vitamin A plasma transporter RBP4 (retinol binding protein-4) of adipose origin was identified as a new adipokine favouring insulin resistance in mice through effects on liver and muscle , which are more likely independent of vitamin A. Among carotenoid/retinoids, RAs appear as the more active on adipokine regulation. In particular, inhibitory effects of RA (all-trans and 9-cis) on the expression/secretion of leptin [17, 32, 33], resistin , and RBP4 specifically of adipose origin  have been described, both in in vivo (in adipose tissue of treated animals) and adipocyte cell models. Resistin and adipose RBP4, as well as hyperleptinemia in the setting of leptin resistance, have been linked to insulin resistance so that the observed effects could be viewed as beneficial. It should be noted, however, that the insulin-sensitising hormone adiponectin has also been shown to be down-regulated in perirenal adipose tissue of mice after acute all-trans RA treatment . β-apo-14′-carotenal also promoted a decrease of adiponectin expression during 3T3-L1 differentiation .
Data on the lipidic metabolism of adipocytes treated with either β-carotene or apocarotenals are scarce. To the best of our knowledge, only studies dealing with all-trans RA have been published. These studies showed that both in in vivo (in treated mice) and mature 3T3-L1 adipocytes, all-trans RA triggered remodelling to reduce lipogenesis and increased oxidative metabolism, as shown by gene expression changes, histological changes and in the case of cultured cells, increases in lipolysis and fatty acid oxidation [50, 51].
Biological properties of β-carotene most probably depend on the complex interplay between (among others factors) β-carotene dosage, physiological state of the organism and genetic make-up. Enzymes involved in β-carotene cleavage clearly play a significant role in its in vivo properties by regulating the nature of the metabolites. The function of BCMO1 as the key enzyme in the production of vitamin A from provitamin A seems well established, as observed in BCMO1 −/− mice and identification of SNPs modulating β-carotene conversion efficiency and β-carotene status. Besides, studying the genetic variation in BCDO2 gene might help to gain information into its physiological function. Adipose tissue, being the main β-carotene storage site of the body and expressing both BCMO1 and BCDO2, appears a priori as an important site for β-carotene actions. Numerous studies have investigated the effect of the different cleavage products of β-carotene on adipose tissue biology. Indeed, it has been well described that retinoic acids strongly impact on adipocyte differentiation, adipokine secretion and lipid metabolism. Some results were also obtained with retinal or β-apo-14′-carotenal, but the effect of intact β-carotene remains largely unknown. To investigate the specific effects of intact β-carotene, the use of the BCMO1 −/− mice would be particularly relevant, since these animals are unable to cleave β-carotene, and therefore absorb and accumulate it in its native form in their tissues. Finally, the influence of genetic variations in carotenoid oxygenase genes on lipid disorders such as liver steatosis, insulin resistance and metabolic syndrome could be investigated to verify whether the observations in BCMO1 −/− mice also apply to the human situation (thereby confirming the role of BCMO1 in lipid metabolism). These data should provide new insights on the mechanisms of carotenoids in disease prevention.
The authors acknowledge the European Nutrigenomics Network NuGO for funding the “Carotenoids” focus team. They are grateful to Drs Aldona Dembiska-Kiec (JUMC Krakow, Poland), Patrick Borel (INRA 1260 Marseille, France), Chris Evelo (BiGCat Maastricht, The Netherlands), Andreu Palou and Joan Ribot (UIB, Spain) for their comments about the manuscript.
Conflict of interest statement
The authors declare having no conflict-of-interest.
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