Vitamin C

All overweight and obese patients have vitamin C status that correlated inversely with BMI, and serum vitamin C levels were significantly lower in obese than overweight patients. Moreover, serum vitamin C levels were lower in individuals who have hypertriglyceridaemia and low levels of high-density lipoprotein-cholesterol (HDL-C) as compared with those having normal triglyceride and HDL-C levels. Low vitamin C status was the independent risk factor for obesity and lipid metabolic dysfunction^{(Reference Yin, Du and Sheng19)}. However, the effects of vitamin C on lipid metabolism, and vitamin C supplementation on lipid profile, are unclear. In rodent, vitamin C was found to reduce visceral obesity through activating peroxisome proliferator-activated receptor-α (PPARα)^{(Reference Lee, Ahn and Shin20)}. But human studies on the effects of vitamin C on adipocytes, including differentiation, triglyceride accumulation and lipolysis inhibition are conflicting^{(Reference Garcia-Diaz, Lopez-Legarrea and Quintero21)}, as detailed below.

A meta-analysis of 13 RCTs indicated that a minimum 4 weeks of at least 500 mg daily vitamin C supplementation can significantly decrease serum low-density lipoprotein-cholesterol (LDL-C) and triglyceride concentrations^{(Reference McRae22)}. However, participants in those RCTs were not obese but were either healthy, elderly, diabetic or have hyperlipidaemia. Another meta-analysis of RCTs conducted subsequently to ascertain the effects of vitamin C on blood total cholesterol, LDL-C, HDL-C and triglyceride concluded that vitamin C supplementation has no significant effect on lipid profile^{(Reference Ashor, Siervo and van der Velde23)}. Although vitamin C supplementation did not change blood lipids concentrations significantly, it has benefited specific groups such as lowering the total cholesterol of younger participants, the LDL-C of healthy participants and the triglyceride of diabetics while increasing the HDL-C in diabetics. The authors, therefore, concluded that vitamin C supplement provided more benefit to individuals with higher baseline levels of total cholesterol and triglyceride^{(Reference Ashor, Siervo and van der Velde23)}. Nevertheless, similar to the earlier meta-analysis^{(Reference McRae22)}, the adult participants in the study were non-obese.

It appears that patients who have altered metabolic parameters require high dose and chronic consumption of vitamin C if they were to gain any potential benefits of vitamin C. This is due partly to the fact that vitamin C does not accumulate in the body and the excess is eliminated immediately through urine^{(Reference Levine, Conry-Cantilena and Wang24)}. Diabetic patients administered 1000 mg daily oral vitamin C for 4 months showed improvement in whole body glucose disposal and non-oxidative glucose metabolism^{(Reference Paolisso, Balbi and Volpe25)}, but 800 mg daily intake of vitamin C for 4 weeks did not improve glucose metabolism or insulin resistance^{(Reference Chen, Karne and Hall26)}. This means that if the dose of vitamin C is insufficient to fully replenish the low baseline level of vitamin C in these patients^{(Reference Ford, Mokdad and Giles27)}, it is ineffective in improving endothelial dysfunction and insulin resistance. The same condition may apply to obesity.

In obesity, white AT overgrowth leads to increased production of pro-inflammatory cytokines including TNF-α, interleukin-6 (IL-6), MCP-1 and inducible nitric oxide synthase (iNOS), activation of inflammatory pathways of IкB kinase (IKK-β) and nuclear factor-кB (NF-кB), mitochondrial dysfunction, reactive oxygen species (ROS) overproduction and depletion of the antioxidant defense^{(Reference Garcia-Diaz, Campion and Milagro28)}. Oxidative stress has been associated with low grade chronic inflammation and insulin resistance^{(Reference Garcia-Diaz, Campion and Milagro28)}. While it might not be easy to demonstrate the causal effect of the relationship, it is believed that inflammation occurs during the early stage of obesity development, followed by an enhanced oxidative stress status^{(Reference Vahid, Rahmani and Davoodi13,Reference Matsuda and Shimomura29)} . Therefore, dietary supplements which have anti-inflammatory and/or antioxidant properties maybe beneficial in the management of metabolic derangement in obesity.

Vitamin C is an antioxidant due to its ability to donate electron. In isolated rat adipocytes, vitamin C reduced intracellular and extracellular ROS production^{(Reference Garcia-Diaz, Campion and Milagro28)}. In vitro, vitamin C inhibited the activation of NF-кB signalling^{(Reference Bowie and O'Neill30)} and IKK-β enzyme^{(Reference Carcamo, Pedraza and Borquez-Ojeda31)}. In vitro and in vivo animal studies showed that vitamin C increased the production of lipoxin A4, an anti-inflammatory and antioxidant^{(Reference Das32)}. Broiler chicks supplemented with a vitamin C-rich diet have decreased hepatic mRNA expressions of IL-1β, IL-6, interferon-γ, Toll-like receptor-4 and heat shock protein 70 compared with those fed with a control diet. Lipid peroxidation in the serum and liver of these animals was also significantly decreased^{(Reference Jang, Ko and Moon33)}. Data of the abovementioned effects of vitamin C supplementation on human, however, are not available, and Abdali et al. ^{(Reference Abdali, Samson and Grover34)} thought that vitamin C is of marginal benefits to obese and diabetic patients.

Vitamin B₁ (thiamine)

Thiamine is a water-soluble vitamin that is not stored substantially in the body. Many morbidly obese patients are thiamine-deficient, and the prevalence of thiamine deficiency was 7–8 folds higher in African Americans and Hispanics than in Caucasian^{(Reference Flancbaum, Belsley and Drake35)}. The reason for racial differences is unknown. Thiamine catalyses several key biochemical reactions involved in glucose metabolism. This means that metabolism of a sugar-high diet requires high amount of thiamine. Obese patients who consume energy dense and high sugar content diet may, therefore, have much higher thiamine needs^{(Reference Kerns, Arundel and Chawla36)}, and accelerated thiamine depletion during glucose metabolism. Thiamine deficiency leads to impairment in insulin synthesis and secretion^{(Reference Mee, Sekar and Subramanian37)}. Severe deficiency is associated with increased endothelial nitric oxide synthase (eNOS) production, intercellular adhesion molecule-1 (ICAM-1) levels and ROS production^{(Reference Page, Laight and Cummings38)}.

Thiamine has antioxidant properties. In vitro studies showed that thiamine supplementation inhibited lipid peroxidation^{(Reference Lukienko, Mel'nichenko and Zverinskii39)}, and limited hyperglycaemia-induced von Willebrand factor secretion from bovine aortic endothelial cells thereby endothelial cell dysfunction^{(Reference Ascher, Gade and Hingorani40)}. Given the high rates as well as the consequences of thiamine deficiency in obese and diabetic patients, Via^{(Reference Via16)} opined that thiamine supplementation may be considered in this group of people. However, to date, there is no published data on thiamine requirements in overweight and obese patients, i.e. how much thiamine should patients consume in order to tackle the consequences resulting from thiamine deficiency is unclear. Several reasons might explain this: (1) the ability of a thiamine-rich diet in causing weight loss in obese and overweight individuals has not been demonstrated^{(Reference Keogh, Cleanthous and Wycherley41)}; (2) the lack of studies and evidence of the effectiveness of long-term thiamine supplementation on combating the metabolic changes in obesity; (3) the amount of thiamine needed by obese people may simply be too high since they have high sugar level contributed by insulin resistance and/or energy dense diet, which accelerate thiamine usage, but they already have a low thiamine level in the body, therefore making the approach to increase thiamine level through diet and supplement non-feasible; (4) the beneficial effects of thiamine may be confounded by the body sugar levels; and (5) there is other dietary vitamin that is superior to thiamine in managing body weight, and glucose and lipid metabolism.

Vitamin D

The main function of vitamin D is for the maintenance of bone tissue, and homeostasis of calcium and phosphorus. Extra-skeletal functions of vitamin D include those on the muscular, insulin sensitivity and immune system, to name a few^{(Reference Lips42)}. Moderate vitamin D deficiency leads to increased bone turnover and a greater risk of bone fractures, while severe deficiency causes osteomalacia in adults and rickets in children. Vitamin D deficiency is also associated with visceral adiposity-related metabolic syndrome such as obesity, dyslipidemia, insulin resistance, diabetes, cardiovascular diseases and hypertension^{(Reference Vranić, Mikolašević and Milić43)}. Serum vitamin D status correlates negatively with the BMI of children, adolescents and adults^{(Reference Tang, Zhan and Wei15,Reference McKay, Ho and Jane17)} .

The possible causes for the decreased vitamin D serum level in obesity have been reported in numerous review articles^{(Reference Vranić, Mikolašević and Milić43–Reference Walsh, Bowles and Evans46)}, although as cited in these reviews, the studies of some of those causes were conflicting. The more probable causes of decreased vitamin D in obesity are: (1) vitamin D sequestration in AT – as the amount of AT increases, vitamin D is accumulated and retained in AT, resulting in a lower plasma concentration^{(Reference Wortsman, Matsuoka and Chen47)}; (2) low sunlight exposure^{(Reference Walsh, Bowles and Evans46)} and (3) altered volumetric dilution of vitamin D – vitamin D is distributed into serum, muscle, fat and liver, in which all these compartments are increased in obesity^{(Reference Heaney, Horst and Cullen48)}. These mechanisms suggest that weight loss or reducing visceral adiposity by increasing physical activity for example, and exposure to sunlight will increase circulatory levels of vitamin D. If so, do obese people still need vitamin D supplementation?

A 26 weeks treatment with 7000 IU (175 μg) vitamin D daily did not change body fat accumulation of obese patients as compared to placebo^{(Reference Wamberg, Kampmann and Stødkilde-Jørgensen49)}. In a 12 months RCT, obese patients receiving 2000 IU vitamin D daily and lifestyle-based weight loss programme did not have significant reduction in body weight, body composition, BMI, insulin and C-reactive protein (CRP) levels when compared with the placebo group who received lifestyle-based weight loss programme only^{(Reference Mason, Xiao and Imayama50)}. In the present study^{(Reference Mason, Xiao and Imayama50)} however, the placebo group also did not have significant changes in body weight and body composition between pre-treatment and at 12 months, and possibly because of this, according to the above proposed mechanisms (1) and (3), the group has no significant change in serum vitamin D at 12 months (20 ng/ml). The study group that received vitamin D supplementation has significant elevation in serum vitamin D concentration (35 ng/ml), suggesting that intake of 2000 IU once daily for 12 months is sufficient to increase serum vitamin D in obese patients. Together with the study by Wamberg et al. ^{(Reference Wamberg, Kampmann and Stødkilde-Jørgensen49)}, present evidences do not support vitamin D supplementation in reducing body weight and body composition.

The effects of vitamin D on adipogenesis and lipid accumulation contradict between in vitro studies per se and between in vitro and in vivo studies^{(Reference Dix, Barcley and Wright44)}. In vitro studies using mouse cell lines showed that vitamin D inhibited adipogenesis by down-regulating CCAAT enhancer binding proteins (C/EBP) and PPARγ, and inhibited lipid accumulation by suppressing the expression of sterol regulatory element binding protein 1c (SREBP1c) and LPL. SREBP1c is a protein that promotes the expression of genes involved in glucose metabolism, lipogenesis and fatty acid production. In mouse primary cell culture, however, vitamin D was pro-adipogenic. Pro-adipogenic effects of vitamin D were also observed in in vivo animal models. To date, there is no evidence to suggest that vitamin D supplementation suppresses adipogenesis signalling pathways in human. Studies of the effects of vitamin D on lipid profiles of obese patients are available but have reported conflicting results – a placebo-controlled RCT showed that vitamin D supplement has no effect on patients’ plasma triglyceride, HDL-C and total cholesterol levels^{(Reference Wamberg, Kampmann and Stødkilde-Jørgensen49)}. But in a meta-analysis, vitamin D treatment increased HDL-C and oral glucose insulin sensitivity and decreased triglyceride but it also increased LDL-C^{(Reference Manousopoulou, Al-Daghri and Garbis51)}.

In terms of the anti-inflammatory effects of vitamin D, Wamberg et al. ^{(Reference Wamberg, Kampmann and Stødkilde-Jørgensen49)} reported that the consumption of 7000 IU vitamin D daily for 26 weeks did not significantly decrease circulatory inflammatory markers such as CRP, IL-6, MCP-1, leptin and adiponectin. In other studies, intake of 40 000 IU vitamin D weekly for one year decreased serum IL-6 but increased CRP, and demonstrated no effects on insulin resistance, TNF-α^{(Reference Beilfuss, Berg and Sneve52)}, ICAM-1, interferon-γ, MCP-1 and CRP^{(Reference Jorde, Sneve and Torjesen53)} in overweight and obese patients. Despite these contradictory findings, since patients with BMI above 38⋅4 kg/m² have baseline vitamin D that correlated negatively with serum levels of leptin and resistin, and positively with serum adiponectin levels, some researchers suggest consuming vitamin D to improve AT function and prevent obesity-related diseases^{(Reference Stokić, Kupusinac and Tomic-Naglic54)}, and this recommendation may be relevant to morbidly obese patients. However, if the mechanisms that cause serum vitamin D reduction in obesity are as reported in the literature, any means of reducing body weight would increase serum vitamin D. Moreover, there are very few vitamin D-rich sources, and the amount of vitamin D from the same source but of different origin could vary and could be relatively low^{(Reference Midtbø, Nygaard and Markhus55)}.

Vitamin A

Dietary vitamin A was found to be associated significantly with plasma retinol levels^{(Reference Wei, Peng and Cao56)}, while inadequate intake is the major factor contributing to vitamin A deficiency^{(Reference Reifen57)}. Overweight and obese individuals who were deficient in serum levels of vitamin A and vitamin D, were said to have high calorie malnutrition^{(Reference McKay, Ho and Jane17)}. The BMI of obese adults and children correlated negatively with serum vitamin A levels^{(Reference Wei, Peng and Cao56–Reference Botella-Carretero, Balsa and Vázquez58)}. A significantly lower serum vitamin A concentration in obese children than that of normal weight children was also associated with increased waist circumference, fasting plasma glucose and triglyceride, and decreased HDL-C^{(Reference Wei, Peng and Cao56)}. Research to understand the effects of vitamin A on obesity has been done extensively on its precursor, carotenoids. This may be explained by pre-clinical and clinical studies, which indicated that carotenoids and carotenoids derivatives prevented abdominal adiposity, and have anti-inflammatory and antioxidant effects. Moreover, intact carotenoid molecules and carotenoid cleavage products may have additional biological activities whose relevance for human health are still unknown^{(Reference Bonet, Canas and Ribot59)}.

There are over 600 carotenoids present in nature, of which some 50 are found in human diet, mainly fruits and vegetables. But only about half of those found in the diet are detected in human blood and tissue^{(Reference Krinsky and Johnson60,Reference Moran, Mohn and Hason61)} . The most abundant carotenoids in human serum are α-carotene, β-carotene, lycopene, lutein, zeaxanthin and β-cryptoxanthin^{(Reference Moran, Mohn and Hason61)}. Retinol may be generated de novo from α-carotene, β-carotene and β-cryptoxanthin^{(Reference Bonet, Canas and Ribot59)}. Carotenoids are accumulated mainly in the liver and adipose tissues^{(Reference Rodriguez-Concepcion, Avalos and Bonet62)}. The tissue distribution of carotenoids implies their potential effects on the metabolic processes within these tissues^{(Reference Eggersdorfer and Wyss63)}.

Carotenoids are lipid-soluble and widely found in plant-based sources. Besides fruits and vegetables, carotenoids are available in commonly consumed food such as bread, eggs, milk, beverages, fats and oils^{(Reference Rao and Rao64)}. Carotenoids insufficiency was reported in adults and children with obesity^{(Reference Yao, Yan and Guo65)}. A study by Harari et al. ^{(Reference Harari, Coster and Jenkins66)} showed that all the five serum carotenoids measured (α-carotene, β-carotene, lutein, lycopene and ζ-carotene) were significantly lower in adult obese patients compared with non-obese individuals. These obese patients have higher total body fat and central fat, but lower HDL-C, and reduced insulin sensitivity. Similar to adults, serum carotenoids (α-carotene and β-carotene) of obese children correlated negatively with BMI, waist circumference, fat mass and triglyceride, and positively with HDL-C^{(Reference Farook, Reddivari and Mummidi67)}. In healthy adults, serum total and specific carotenoid concentrations were associated inversely with CRP, MCP-1 and TNF-α^{(Reference Jing, Xiao and Dong68)}. In school-aged children, plasma β-carotene was associated negatively with plasma IL-6 levels^{(Reference Rodriguez-Rodriguez, Lopez-Sobaler and Navia69)}. Obese individuals who have significantly lower circulating carotenoids than healthy subjects may, therefore, be exposed to a higher risk of inflammation.

A recent meta-analysis^{(Reference Yao, Yan and Guo65)} reported that carotenoids supplementation in overweight and obese individuals might contribute to the reduction in body weight, BMI, waist circumference and total cholesterol while increasing HDL-C. However, carotenoids have no effect on fat ratio, LDL-C and triglyceride concentrations. Among the six carotenoids present abundantly in serum, only α-carotene, β-carotene and β-cryptoxanthin have pro-vitamin A activity. The importance of the other carotenoids in human nutrition is rather limited^{(Reference Grune, Lietz and Palou70)}. Because β-carotene oxygenase 1 is the sole enzyme responsible for the conversion of carotenoids to vitamin A, significant interest, hence research has been conducted on β-carotene to delineate its mechanism of action on adipogenesis and inflammation.

In vitro and in vivo animal studies showed that β-carotene through its cleavage product, β-apo-14′-carotenal, inhibited adipogenesis through repression of PPARα, PPARγ and retinoid X receptor-α activation^{(Reference Ziouzenkova, Orasanu and Sukhova71)}. β-carotene through its metabolite retinoic acid, decreased the expression of PPARγ and C/EBP-α, and the lipid content of mature adipocytes. β-carotene administration, through increasing retinoic acid signalling, down-regulated PPARγ expression in white AT of vitamin A-deficient mice^{(Reference Lobo, Amengual and Li72)}. β-carotene exhibited anti-inflammatory effects in adipocytes by limiting TNF-α-induced ROS production as well as alterations in the expression of genes related to insulin sensitivity, including adiponectin, adipocyte lipid-binding protein, glucose transporter-4, PPARγ2 and adiponectin protein^{(Reference Kameji, Mochizuki and Miyoshi73)}. Also in adipocytes, β-carotene inhibited oxidative stress-induced adiponectin dysregulation, increased MCP-1 expression and NF-кB activation^{(Reference Cho, Kim and Kim74)} (Fig. 1). As to whether the effects of anti-adipogenesis and anti-inflammation of β-carotene are seen in human have not been established yet.

Fig. 1.

The effects of carotenoids and β-carotene on obesity. In human studies, carotenoids were reported to improve weight, body composition and HDL-C in obese subjects. In pre-clinical studies, β-carotene's cleavage product, β-apo-14′-carotenal inhibited adipogenesis through suppressing PPARα, PPARγ and RXR-α activation. The metabolite of β-carotene, retinoic acid was reported to inhibit adipogenesis and inflammation. These effects were seen in in vitro and in vivo studies. ALBP, adipocyte lipid-binding protein; C/EBP-α, CCAAT enhancer binding proteins; GLUT4, glucose transporter-4; HDL-C, high-density lipoprotein-cholesterol; MCP-1, macrophage chemoattractant protein-1; NF- кB, nuclear factor-кB; PPARα, peroxisome proliferator-activated receptor-α; PPARγ, peroxisome proliferator-activated receptor-γ; ROS, reactive oxygen species; RXR-α, retinoid X receptor-α; TNF-α, tumor necrosis factor-α; WAT, white adipose tissue.