Over the past decades, obesity has become a rising health problem as the accessibility to high calorie, low nutritional value food has increased. Research shows that some bioactive components in fruits and vegetables, such as carotenoids, could contribute to the prevention and treatment of obesity. Some of these carotenoids are responsible for vitamin A production, a hormone-like vitamin with pleiotropic effects in mammals. Among these effects, vitamin A is a potent regulator of adipose tissue development, and is therefore important for obesity. This review focuses on the role of the provitamin A carotenoid β-carotene in human health, emphasizing the mechanisms by which this compound and its derivatives regulate adipocyte biology. It also discusses the physiological relevance of carotenoid accumulation, the implication of the carotenoid-cleaving enzymes, and the technical difficulties and considerations researchers must take when working with these bioactive molecules. Thanks to the broad spectrum of functions carotenoids have in modern nutrition and health, it is necessary to understand their benefits regarding to metabolic diseases such as obesity in order to evaluate their applicability to the medical and pharmaceutical fields.

Atherosclerosis is characterized by the pathological accumulation of cholesterol-laden macrophages in the arterial wall. Atherosclerosis is also the main underlying cause of cardiovascular diseases (CVDs), and its development is largely driven by elevated plasma cholesterol. Strong epidemiological data find an inverse association between plasma β-carotene with atherosclerosis, and we recently showed that β-carotene oxygenase 1 (BCO1) activity, responsible for β-carotene cleavage to vitamin A, is associated with reduced plasma cholesterol in humans and mice. In this study, we explore whether intact β-carotene or vitamin A affect atherosclerosis progression in the atheroprone low-density lipoprotein receptor (LDLR) - deficient mice. In comparison to control-fed Ldlr-/- mice, β-carotene-supplemented mice showed reduced atherosclerotic lesion size at the level of the aortic root and reduced plasma cholesterol levels. These changes were absent in Ldlr-/-/Bco1-/- mice, despite accumulating β-carotene in plasma and atherosclerotic lesions. We discarded the implication of myeloid BCO1 in the development of atherosclerosis by performing bone marrow transplant experiments. Lipid production assays found that retinoic acid, the active form of vitamin A, reduced the secretion of newly synthetized triglyceride and cholesteryl ester in cell culture and mice. Overall, our findings provide insights into the role of BCO1 activity and vitamin A in atherosclerosis progression through the regulation of hepatic lipid metabolism.

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β-carotene oxygenase 1 (BCO1) catalyzes the cleavage of β-carotene to form vitamin A. Besides its role in vision, vitamin A regulates the expression of genes involved in lipid metabolism and immune cell differentiation. BCO1 activity is associated with the reduction of plasma cholesterol in humans and mice, while dietary β-carotene reduces hepatic lipid secretion and delays atherosclerosis progression in various experimental models. Here we show that β-carotene also accelerates atherosclerosis resolution in two independent murine models, independently of changes in body weight gain or plasma lipid profile. Experiments inBco1-/-mice implicate vitamin A production in the effects of β-carotene on atherosclerosis resolution. To explore the direct implication of dietary β-carotene on regulatory T cells (Tregs) differentiation, we utilized anti-CD25 monoclonal antibody infusions. Our data show that β-carotene favors Treg expansion in the plaque, and that the partial inhibition of Tregs mitigates the effect of β-carotene on atherosclerosis resolution. Our data highlight the potential of β-carotene and BCO1 activity in the resolution of atherosclerotic cardiovascular disease.

Introduction: Macrophages are key players in atherosclerosis. Classically-activated (M1) macrophages show a pro-inflammatory phenotype, whereas alternatively-activated (M2) are anti-inflammatory. The M1/M2 balance in atherosclerosis determines the fate of the lesions and strategies to increase M2-like macrophages entail promising therapeutic candidates. Retinoic acid (RA), the transcriptionally active form of vitamin A, delays atherosclerosis progression in mice and has been investigated as a modulator of macrophage polarization. Hypothesis: RA modulates macrophage polarization by inducing M2-like responses. Methods: Bone marrow-derived macrophages from three wild-type C57BL/6J mice were differentiated (M0) and stimulated with LPS/IFNγ (M1) or IL-4 (M2) for 24h, followed by 6h exposure to 1 μM RA or vehicle (DMSO). RNAseq and gene enrichment analysis were performed. Efferocytosis assays were performed by co-culture of apoptotic Jurkat cells with treated macrophages and subsequent analysis by flow cytometry. Autophagy flux and lysosomal protein breakdown rate were also analyzed. Results: RNAseq showed that RA induced changes in 1,485 genes in M2 macrophages, while 821 and 227 genes were significantly regulated in M0 and M1, respectively. Given the lower impact of RA on M1, we focused our subsequent analyses on M0 and M2. Arginase 1 , a well-known marker of M2 activation, was significantly upregulated by RA at both the mRNA and the protein levels in M0 and M2. Scavenger receptors pathway was regulated in M2 exposed to RA, and efferocytosis assays showed that this group had significantly the highest efferocytotic capacity. Autophagy and Lysosome pathways were also significantly over-represented in M2 treated with RA, although autophagy flux and protein breakdown rate were not differentially affected by RA in M2 or M0 macrophages. Conclusions: Transcriptomic analyses showed a higher response of M2 macrophages to RA, compared to M0 and M1. Functional assays revealed that RA increased efferocytosis in M2 macrophages, a hallmark of alternative activation. Our results suggest that RA skews macrophages' polarization and it might promote an M2-like phenotype, especially in macrophages exposed to IL4, enhancing alternative activation.

β-carotene oxygenase 1 (BCO1) catalyzes the cleavage of β-carotene to form vitamin A. Besides its role in vision, vitamin A regulates the expression of genes involved in lipid metabolism and immune cell differentiation. BCO1 activity is associated with the reduction of plasma cholesterol in humans and mice, while dietary β-carotene reduces hepatic lipid secretion and delays atherosclerosis progression in various experimental models. Here we show that β-carotene also accelerates atherosclerosis resolution in two independent murine models, independently of changes in body weight gain or plasma lipid profile. Experiments in Bco1-/- mice implicate vitamin A production in the effects of β-carotene on atherosclerosis resolution. To explore the direct implication of dietary β-carotene on regulatory T cells (Tregs) differentiation, we utilized anti-CD25 monoclonal antibody infusions. Our data show that β-carotene favors Treg expansion in the plaque, and that the partial inhibition of Tregs mitigates the effect of β-carotene on atherosclerosis resolution. Our data highlight the potential of β-carotene and BCO1 activity in the resolution of atherosclerotic cardiovascular disease.

β-carotene oxygenase 1 (BCO1) catalyzes the cleavage of β-carotene to form vitamin A. Besides its role in vision, vitamin A regulates the expression of genes involved in lipid metabolism and immune cell differentiation. BCO1 activity is associated with the reduction of plasma cholesterol in humans and mice, while dietary β-carotene reduces hepatic lipid secretion and delays atherosclerosis progression in various experimental models. Here we show that β-carotene also accelerates atherosclerosis resolution in two independent murine models, independently of changes in body weight gain or plasma lipid profile. Experiments in Bco1-/- mice implicate vitamin A production in the effects of β-carotene on atherosclerosis resolution. To explore the direct implication of dietary β-carotene on regulatory T cells (Tregs) differentiation, we utilized anti-CD25 monoclonal antibody infusions. Our data show that β-carotene favors Treg expansion in the plaque, and that the partial inhibition of Tregs mitigates the effect of β-carotene on atherosclerosis resolution. Our data highlight the potential of β-carotene and BCO1 activity in the resolution of atherosclerotic cardiovascular disease.

Objectives Androgen imbalance is associated with cardiovascular disease risk but the exact impact on lipid and glucose profile is unknown. Finasteride (FIN) prevents the conversion of testosterone to its active metabolite dihydrotestosterone (DHT) by inhibiting the type II 5alpha-reductase. Our objective is to examine the impact of FIN on cardiovascular disease risk. We hypothesize that FIN delays the progression of atherosclerosis by ameliorating hyperglycemia and dyslipidemia. Methods We used the low-density lipoprotein receptor (LDLR)-deficient (Ldlr−/−) mouse model as a widely regarded model of atherosclerotic plaque development in rodents. Four-week-old male mice (n = 9–15/group) were fed a Western-diet containing 41% fat +0.3% cholesterol with increasing doses of FIN (10 mg/kg, 100 mg/kg, and 1000 mg/kg diet) for 12 weeks. Littermates fed Western-diet without FIN were used as a control group. A week before tissue harvest, mice were subjected to a glucose tolerance test (GTT). At the end of the experiment, mice were sacrificed, and their tissue and body weights were analyzed. A total cholesterol assay was performed at 0, 4, 8, and 12 weeks. Results We examined prostate size, whose growth is DHT dependent, as an indicator of the effect of finasteride in our experimental model. We observed a dose-dependent effect of FIN on prostate size for all the doses (P < .0001), indicating FIN had a physiological impact on these mice. No changes in food intake or circulating transaminase levels were observed, discarding any evidence of food intolerability or hepatic toxicity. FIN did not alter GTT among experimental groups or any other biometric parameter. However, we observed a significant reduction in body weight gain in the high dose group (P = .0027) in comparison to the other experimental groups. Total cholesterol levels at the time of the sacrifice were significantly reduced in the high dose group (P < .0001) in comparison to the other experimental groups. Future experiments will include atherosclerotic plaque characterization of both size and composition. Conclusions Our findings suggest that a high dose of FIN is associated with a reduction of total plasma cholesterol and body weight in Ldlr−/− mice. Funding Sources USDA multistate hatch project (W4002)