Carotenoids and carotenoid conversion products in adipose tissue biology and obesity: Pre-clinical and human studies☆
Introduction
Excessive body fat accumulation is a defining feature of overweight and obesity [1]. These conditions - especially when excess fat is in the visceral area or in ectopic (non-adipose tissue) locations - are associated to health risk factors such as insulin resistance, dyslipidemia, or hypertension that could lead to suffering of metabolic syndrome. The worldwide prevalence of overweight and obesity has doubled since 1980 [2]. Reversal of obesity is difficult once established. The current obesity pandemic, and the recognition that traditional strategies based solely on food restriction and increased physical activity are being ineffective against it, is boosting research in coadjuvant treatments that could effectively complement life-style modifications. In recent years, antiobesity activities of carotenoids and carotenoid derived products have been demonstrated in a number of pre-clinical studies, and molecular mechanisms behind have begun to be unveiled, suggesting these compounds may help obesity prevention and management. Furthermore, there is increasing evidence that endogenous carotenoid and retinoid metabolism may modulate physiological processes connected to body fat regulation.
Carotenoids are isoprenoid pigments in the yellow to red range, synthetized by plants and microorganisms, which contain in their molecule a polyene backbone with a variable number of conjugated double bounds. Carotenoids can be cyclic or acyclic, depending on the presence or absence of end rings in their structure, and can contain exclusively carbon and hydrogen atoms (carotenes) or contain as well oxygen atoms (xanthophylls) [3]. The double bond system confers on carotenoids antioxidant properties and the capability to absorb light in the visible spectrum. Photosynthetic organisms utilize carotenoids for light harvesting, as photoprotectants, and as precursors of signaling molecules [3]. Carotenoids are eaten by animals mainly through fruits and vegetables, and - at least some of them - serve functions in animals, either as intact molecules or following metabolism. Metabolism of carotenoids usually involves the oxidative cleavage - enzymatic or nonenzymatic - of the polyene backbone, at central or eccentric positions, which gives rise to shortened derivatives known as apocarotenoids. It can also involve other reactions, such as modifications of terminal groups. Of the hundreds of carotenoids in nature, ~50 are present in the human diet, and six are ubiquitously found in human serum: β-carotene, α-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin [3]. The colorless carotenoids phytoene and phytofluene are also major carotenoids consistently detected in human plasma and tissues [4].
In mammals, the best known function of carotenoids is to serve as precursors of the natural vitamin A retinoids: retinol, retinaldehyde, and retinoic acid. Provitamin A activity is restricted to carotenoids with at least one unsubstituted β ionone ring, such as β-carotene (considered the most potent vitamin A precursor, since it is the only carotenoid with two unsubstituted β ionone rings), α-carotene, and β-cryptoxanthin. These carotenoids are substrates of β-carotene-15,15′-dioxygenase (BCO1), a cytosolic enzyme that catalyzes their centric oxidative cleavage to release retinaldehyde (retinal), from which all other natural vitamin A retinoids can be produced [5]. The vitamin A retinoids are essential nutrients required for vision (retinaldehyde) and gene expression control relevant to many developmental and physiological processes (mainly retinoic acid). Retinoids can be obtained independent of carotenoids through the intake of preformed vitamin A found in foods of animal origin. In industrialized countries, for instance, it has been estimated that preformed vitamin A accounts for nearly 65% of total human vitamin A intake, carotenoids make up 35% [6]. Ultimately, however, all natural retinoid present in mammals is derived from provitamin A carotenoids, either directly or indirectly through an animal lower in the food chain [7], and retinoids are thus considered a class of apocarotenoids [8]. Mammals express a second carotenoid cleavage enzyme, β-carotene-9′,10′-oxygenase (BCO2), which is a mitochondrial enzyme with a broader substrate specificity that cleaves eccentrically both provitamin A carotenoids and other carotenoids, such as cis lycopene, and the xanthophylls lutein and zeaxanthin, yielding apo-10′-carotenoids. Cumulative evidence indicates that, besides the retinoids, nonretinoid apocarotenoids may also impact cellular functions and influence mammalian health [8].
Adiposity reducing activity has been demonstrated both for provitamin A carotenoids and non-provitamin A carotenoids in animal studies (reviewed in [[9], [10], [11]]). The antiobesity activity of β-carotene in rodents is related to its provitamin A activity [12], in line with proven antiadiposity activities of retinoids (to which we shall refer in more detail later). Nevertheless, carotenoids per se, nonretinoid apocarotenoids, and carotenoid conversion products other than apocarotenoids may also have biological activities of interest in the context of body fat control and metabolic health. In this review, we use the term “carotenoid conversion products” (CCPs) to collectively refer to retinoid and nonretinoid apocarotenoids, as well as other type of natural carotenoid derived metabolites. It should be emphasized that, for most cell model-based and in vivo experimental studies, it remains unknown if it is the parent supplemented compound, a metabolic derivative(s) or both which is/are responsible for observed effects. A simplified overview of the relationships among carotenoids and their metabolites including retinoids is shown in Fig. 1.
Most studies dealing with the antiobesity activity of carotenoids have used rodents as animal models. This is explained because well-established rodent models of genetic and dietary obesity are available and because molecular physiology of body fat control has been most studied in rodents and resembles that in humans. Rodents are omnivorous animals, and laboratory rodent chows do contain carotenoids, coming for instance from dehydrated alfalfa meal [13], whereas the concentration of carotenoids in defined (purified) experimental diets is presumably lower than that in chows. Importantly, oxidative cleavage of carotenoids such as provitamin A carotenoids and lutein is more active in rodents than in humans. Consequently, rodents do not accumulate these carotenoids in plasma and tissues when fed at reasonable, “physiological doses”, whereas humans do accumulate them. The difference has been related to the catalytic properties of the carotenoid cleavage enzymes; for instance, murine BCO2 is more active on lutein in vitro than the human (or the macaque) enzyme [14,15]. Because of this, wild-type rodents are generally considered more suitable models to examine the biological properties of carotenoid cleavage products than of intact carotenoids. However, the scenario may not be equal for all carotenoids. For instance, rodents accumulate lycopene in tissues even when supplemented at low doses (e.g. 0.001% in the diet) and might be a good model to study biological actions of lycopene [16,17].
The antiobesity activity of carotenoids and CCPs has been linked to effects in multiple tissues, which are most likely interrelated effects, as there is extensive cross-talk among tissues in mammals through metabolism and neuroendocrine signaling. Nevertheless, important targets in the antiobesity action of carotenoids and CCPs are the adipose tissues, both white adipose tissue (WAT) and brown adipose tissue (BAT). This is not surprising, considering that adipose tissues play critical physiological and pathological roles in lipid and energy metabolism and obesity, and, at the same time, are relevant sites of carotenoid and retinoid storage and metabolism in mammals [9,11].
This work narratively reviews the connections of carotenoids and CCPs with adipose tissue biology and obesity as revealed by cell and animal intervention studies, studies addressing the role of endogenous retinoid metabolism, and human studies. First, key aspects of adipose tissue biology and of carotenoid and retinoid metabolism in it are introduced (Section 2). Animal studies demonstrating antiadiposiy activity of carotenoids and CCPs are then introduced (Section 3), followed by a compilation of general mechanisms that may be behind this activity and related health end-points (Section 4). The antiadiposity action of carotenoids and CCPs introduced in Section 3 is dissected in Section 5, by reviewing their reported impact on different aspects of WAT and BAT biology, including mechanistic clues when available. Section 6 focuses on reported effects of carotenoids and CCPs on non-adipose tissues that may indirectly affect adipose tissue metabolism and obesity. Human epidemiological and intervention studies relating carotenoids and their derivatives to the control of body fat content are reviewed in Section 7. In Section 8, we consider human genetic variability influencing carotenoid and vitamin A metabolism, particularly in adipose tissue, as a potentially relevant aspect towards personalization of dietary recommendations to prevent or manage obesity and optimize metabolic health. Finally, Section 9 summarizes main findings and highlights aspects for future research.
Section snippets
Overview of adipose tissues functions
WAT is specialized in the storage as triglycerides of excess ingested energy (over the energy needed to meet ongoing expenses), and in the regulated supply of energy to other tissues when needed, in the form of fatty acids resulting from lipolysis of stored triglycerides. WAT expansion occurs both by hyperplasia (increased number) of adipocytes, which implies the proliferation of progenitor cells contained in the adipose depots and the differentiation of the resulting cell progeny into
Carotenoids and carotenoid derivatives with antiadiposity activity in animal intervention studies
Antiadiposity activity has been reported for provitamin A carotenoids, in particular β-carotene [12] and β-cryptoxanthin [43], and certain non-provitamin A carotenoids such as: zeaxanthin [44], lycopene [[45], [46], [47]], the green algal carotenoid siphonaxanthin [48], the marine carotenoids fucoxanthin (reviewed in [49]) and astaxanthin [50,51], and the saffron carotenoids crocetin [52] and crocin [53]. Studies reviewed involving supplementation in post-weaned animals are summarized in Table 1
General mechanisms of carotenoids and carotenoids derivatives action
Mechanisms behind antiobesity, anti-inflammatory and antioxidant effects of carotenoids and CCPs might be multiple, as extensively reviewed elsewhere [3,9,30,72,73], and will only be briefly summarized here (Fig. 2).
First, carotenoids, retinoids and other CCPs can impact gene expression and cell function by acting as direct interacting ligands of transcription factors of the nuclear receptor superfamily, among them notably the canonical retinoic acid receptors (RARs), the retinoid X receptors
White adipogenesis
Adipogenesis refers to the formation of new adipocytes from precursor cells. The process has been studied in depth in clonal white preadipocyte cell lines, such as mouse 3T3-L1 cells, and it can be recapitulated in primary cultures established from the stromal/vascular fraction isolated from fat depots (which contains preadipocytes and perivascular adipocyte progenitor cells), or mouse embryonic fibroblasts (MEFs), among other models. Adipogenesis takes place in vivo throughout life, to account
Activities of carotenoids and carotenoid derivatives in non-adipose tissues may affect adipose tissue metabolism and obesity
By modulating nutrient partitioning and the secretion of adipokines, the activity of carotenoids and CCPs (notably vitamin A retinoids) in adipose tissues may elicit adipose-driven protective effects against obesity and the metabolic syndrome involving other key metabolic tissues, such as skeletal muscle, the liver or the brain. Moreover, as further reviewed in this section, dietary carotenoids and retinoids reach those organs directly, where they also regulate metabolic pathways and the
Human epidemiological and intervention studies linking carotenoids and carotenoid derivatives to the control of body adiposity
Evidence of a relationship of carotenoids with human obesity and related health parameters comes mainly from epidemiological studies. Many studies have reported lower serum carotenoids in overweight and obese children, adolescents and adults, and an inverse association between carotenoids concentrations in blood and measures of obesity, such as BMI or waist circumference, in some cases even after adjusting for potential confounders such as the intake of fruit and vegetables, fat or fiber, among
Relevance of genetic variants to carotenoid and vitamin A metabolism in adipose tissue in humans
Genetic variation in or near genes involved in carotenoid uptake, transport and metabolism has been shown to be associated in humans with circulating carotenoids levels, both basal and after a test meal ingestion [262,263]. Genetic variation in some of these same genes and additional ones influences as well vitamin A status and vitamin A bioavailability [264]. Most of the literature on this topic focuses on carotenoid intestinal absorption and management in the enterocytes. However, it is
Final considerations and future research
A connection of carotenoids and carotenoids derivatives with the energy homeostasis system of mammals is well established. This connection implicates the natural vitamin A retinoids (which ultimately all come from carotenoids), but extends beyond the latter to include as well non-provitamin A carotenoids, nonretinoid apocarotenoids, and certain nonapocarotenoid derivatives. For these different but related types of compounds, metabolic health promoting activities usually linked to an
Credit author statement
All authors contributed to different parts of the work.
Declaration of competing interest
Authors have no interest to declare.
Acknowledgements
The authors acknowledge funding support from the Spanish Government (grant PGC2018-097436-B-I00; Agencia Estatal de Investigación, MICIU/FEDER, EU). The group is a member of the European COST-Action EUROCAROTEN (CA15136; EU Framework Programme Horizon 2020), and the Spanish Network of Excellence CaRed (grant BIO2017-90877-REDT; Agencia Estatal de Investigación, MICIU/FEDER, EU). CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERobn) is an initiative of the ISCIII (Spanish Government).
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This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.