Onion Peel Extract Increases Erythrocyte Membrane n-3 Fatty Acids in Overweight and Obese Korean Subjects

Abstract

The association between obesity and erythrocyte fatty acids (FAs) has been suggested; however, there have been no studies on the effects of onion peel extract (OPE) on the composition of erythrocyte FAs. This study aimed to investigate the effects of OPE on the composition of erythrocyte FAs in overweight and obese subjects. This was a randomized, double-blind, and placebo-controlled trial conducted in overweight and obese Korean subjects. The placebo and OPE groups were taking placebo capsule or OPE capsule twice per day for 12 weeks. Body composition and fat distribution were measured using dual-energy X-ray absorptiometry. The OPE group showed significantly reduced body weight, body mass index, body fat mass, and percentage of body fat mass. After 12 weeks, eicosapentaenoic acid and monounsaturated FAs of the placebo group were significantly lower at baseline. Consumption of OPE ameliorated the decreasing polyunsaturated n-3 polyunsaturated FA (PUFA) n-3 and increasing PUFA n-6, which prevented an increased n-6/n-3 ratio. The changes in arm fat percentage (ARFATP), trunk fat percentage, and total fat percentage (FATP) were negatively correlated with the change in PUFA n-3. In addition, increased erythrocyte docosahexaenoic acid was associated with decreased ARFATP and FATP. These results suggest that OPE has beneficial effects on obesity by regulating erythrocyte n-6/n-3 ratio and preventing fat accumulation in various body regions.

Introduction

The World Health Organization (WHO) indicated that the underlying causes of obesity and overweight are an energy imbalance between calories ingested and calories expended.¹ Excessive caloric intake, lack of exercise, and sedentary lifestyle have rapidly increased the prevalence of obesity and its related comorbidities, such as hyperlipidemia, metabolic syndrome, cardiovascular diseases (CVDs), and type 2 diabetes mellitus.² According to the WHO, 39% of adults ≥18 years of age (39% of men and 40% of women) were overweight, and ∼13% of the world's adult population (11% of men and 15% of women) were obese in 2016.¹ In addition, the worldwide prevalence of obesity nearly tripled between 1975 and 2016.¹ The fat distribution in specific regions may be more important for individual health outcome than their relative overall fat.³ Among fat depots, excess abdominal fat, such as android and trunk, is associated with increased risk of atherogenesis, CVDs, and high morbidity and mortality.⁴

Polyunsaturated fatty acids (PUFAs) are composed of cell membranes that maintain their fluidity and sensitiveness to free radical. PUFA n-3 are crucial components of cellular functions that regulate several metabolic pathways.⁵ They are effective in decreasing the risk of abnormal heartbeat, reducing triglyceride levels, and slowing the development of atherosclerotic plaque that reduces the risk of vascular disease.⁵

Arachidonic acid (20:4 n-6, AA) can be inhibited by PUFA n-3 at multiple steps.^6,7 PUFA n-6 increases the synthesis of cellular triglyceride by increasing membrane permeability, whereas PUFA n-3 stimulates fat oxidation in the skeletal muscle and liver.^6,7 Thus, the maintenance of lower n-6/n-3 ratio should be considered in the management of obesity. Some studies have verified that PUFA n-3 are associated with body composition.^8,9 In a 3-week intervention trial among healthy subjects, replacement of 6 g of visible fat with 6 g of fish oil (n-3 PUFAs) significantly reduced body fat mass (BFM) and stimulated lipid oxidation, but did not change body weight.⁸ Flachs et al. ⁹ reported that eicosapentaenoic acid (C20:5n3, EPA) and docosahexaenoic acid (C22:6n3, DHA) can inhibit adipogenesis through enhancement of β-oxidation and upregulation of mitochondrial biogenesis in C57BL/6J mice. Compared with dietary fat intake, measurements of erythrocyte fatty acids (FAs) may be a more stable indicator of long-term intake of dietary fat.¹⁰ Dietary trans FAs were also positively correlated with erythrocyte trans FA contents (r = 0.44; P < .01).¹¹

Onion (Allium cepa L.) peel has been reported to have powerful antioxidant effects due to its several phenolic compounds, including ferulic acid, gallic acid, protocatechuic acid, kaempferol, and quercetin, which are higher than in its other parts.¹² Quercetin and its glycosides are the major flavonols in onion, which are mainly found in onion skin and may contribute to the production of yellow and brown skins in different varieties of onions.¹³ Yellow onion peel contains ∼40 times more quercetin than the other edible parts.¹⁴ Although onion peels have effective properties, they are usually discarded from the edible part. As a result, many efforts are being made to reuse onion peels. Onion peel extract (OPE) has been reported to have antiobesity effects by modulating expressions of genes involved in β-oxidation, thermogenesis, and lipid metabolism in adipose tissue of high-fat-fed rats.¹⁵ OPE also reduces systolic blood pressure and serum cholesterol levels and increases insulin-sensitizing properties resulting in antidiabetic effect.^16
–18 Moreover, OPE has anticancer in vitro and in vivo effects.¹⁹

These findings suggest that OPE could play a beneficial role in the improvement of erythrocyte FA composition by reducing oxidative stress and ameliorating fat accumulation. However, the beneficial effects of quercetin-rich OPE on erythrocyte FA composition in animal and clinical trials have not been fully investigated. Therefore, this study aimed to evaluate the effects of 12-week OPE supplementation on erythrocyte membrane FA composition in overweight and obese Koreans.

Materials and Methods

OPE preparation

Placebo and OPE capsules were processed using the method proposed by Kim et al. ²⁰ The onion peels were obtained from Changnyeong, Korea. They were washed three times, extracted with 60% ethanol (50°C, 3 h), filtered, concentrated to 2.4 Bx, and powdered. Previous research has demonstrated the composition of OPE.²¹ Total polyphenol (TP), total flavonoid (TF), and quercetin were 681.7, 372.0, and 286.0 mg/g of OPE powder, respectively.²¹ Finally, OPE capsules were adjusted to contain 119.2 mg of TP, 65.0 mg of TF, and 50.0 mg of quercetin per capsule, and the placebo capsules are composed of dextrin only.

Ethics statement

This study was conducted according to the guidelines laid down in the Declaration of Helsinki and all procedures involving human subjects were approved by the Institutional Review Board of Kyung Hee Medical Center (KMC IRB 1304-03-C1).

Subjects and experimental design

A 12-week randomized, double-blind, placebo-controlled clinical trial was conducted. Sixty-one overweight and obese subjects (body mass index [BMI], >23 kg/m²) were recruited. Exclusion criteria were as follows: hypertension, diabetes mellitus (DM), CVDs, kidney disease, depressive disorder, medical or surgical illness within 3 months of enrolment, and intake of dietary restricted drugs or participation in diet programs within 30 days of enrolment. Power calculations to determine required sample size were conducted using GPower (Version 3.1.). All subjects were randomly divided into two groups by means of the research randomizer (www.randomizer.org/form.htm). All subjects were provided with either the capsule containing dextrin only (placebo group, n = 30) or the OPE capsule containing 50 mg of quercetin, 119.2 mg of TP, and 65.0 mg of TF (OPE group, n = 31) twice per day for 12 weeks. All subjects signed the informed consent before participation.

Anthropometric measurement and analysis of fat distribution

For each study subject, anthropometric data and fat distribution were measured twice, at the baseline and endpoint. Weight and height were measured, and BMI was calculated as kg/m². The percentage of fat in the arm, leg, trunk, and android was determined using dual-energy X-ray absorptiometry (LUNAR Prodigy; General Electric Co., Madison, WI, USA).

Blood biochemical and erythrocyte membrane FA analysis

At the baseline and endpoint of the trials, blood samples were collected after a 10-h overnight fasting. The blood was centrifuged at 1500 g for 15 min to separate the plasma and erythrocyte, which was stored at −80°C for further analysis. Erythrocyte FAs were measured by gas–liquid chromatography.²²

Statistical analysis

All data are expressed as the mean ± standard deviation. Intragroup changes of fat distribution and erythrocyte FA composition values were determined before and after 12 weeks using paired t-test. The differences between the placebo and OPE groups were assessed using t-test, and statistical significance was defined as P < .05. Statistical analysis was performed with IBM SPSS statistics version 24 software package (IBM Corp., Armonk, NY, USA).

Results

General characteristics

Body compositions of the placebo and OPE groups are shown in Table 1. In case of the OPE group, body weight (P = .013), BMI (P = .031), BFM (BFM; P = .031), and percentage of body fat mass (PBFM; P = .024) were significantly different after OPE supplementation. Subjects in the placebo group did not show significant difference in their body weight, BMI, BFM, and PBFM as compared with the baseline. No significant intergroup differences were found in the body weight, PBFM, and BMI. Consumption of OPE did not significantly affect fat-free mass and BFM at the endpoint compared with the baseline.

Table 1.

Anthropometric Measurement of Subjects During 12 Weeks of Intervention

	Placebo (n = 30)				Onion peel extract (n = 31)
	Baseline	12 Weeks	Change	P ^a	Baseline	12 Weeks	Change	P ^a	P ^b
Age	43.2 ± 8.3				43.3 ± 8.7
Height (cm)	162.5 ± 7.9				162.0 ± 8.0
Weight (kg)	69.6 ± 9.5	69.5 ± 9.1	−0.1 ± 2.2	.836	70.8 ± 10.7	69.6 ± 11.1	−1.2 ± 2.4	.013	.076
BMI (kg/m²)	26.3 ± 2.5	26.3 ± 2.4	0.0 ± 0.8	1.000	26.9 ± 3.2	26.5 ± 3.1	−0.4 ± 0.9	.031	.102
BFM (kg)	25.4 ± 4.6	24.7 ± 4.2	−0.7 ± 2.8	.154	26.0 ± 6.3	25.3 ± 6.3	−0.7 ± 1.7	.031	.963
PBFM (%)	37.8 ± 4.8	37.5 ± 4.8	−0.3 ± 1.3	.219	38.7 ± 6.8	38.0 ± 6.8	−0.6 ± 1.5	.024	.385
FFM (kg)	41.3 ± 7.4	40.5 ± 9.4	−0.8 ± 5.6	.430	41.3 ± 7.9	41.1 ± 7.9	−0.1 ± 0.8	.327	.514

Values are mean ± standard deviation.

P-values within group were statistically analyzed by paired t-test.

P-values between groups were statistically analyzed by t-test.

BFM, body fat mass; BMI, body mass index; FFM, fat-free mass; PBFM, percent body fat mass.

PUFA composition of the erythrocyte membranes

The FA profiles of the erythrocyte membranes are summarized in Table 2. No significant difference was observed among oleic acid (C18:1n9), linoleic acid (C18:2n6, LA), α-linolenic acid (C18:3 n6, ALA), gamma-linolenic acid (C18:3n6, GLA), AA, saturated FA (SAT), monounsaturated FA (MUFA), and PUFA values between the two groups. Compared with the baseline, EPA (P = .016) and MUFA (P = .022) of the placebo group were significantly lower, whereas no significant difference was noted in the OPE group between the baseline and after 12 weeks. PUFA n-6 decreased in the OPE group, but was not significantly different in the placebo group. PUFA n-6/n-3 ratio significantly increased in the OPE group, compared with the baseline (P = .048). The intergroup PUFA n-3 and PUFA n-6/n-3 ratio had a significant difference. Consumption of OPE for 12 weeks ameliorated decreasing of PUFA n-3 and increasing PUFA n-6, resulting in the prevention of increased n-6/n-3 ratio.

Table 2.

Changes in Erythrocyte Fatty Acids of Subjects

	Placebo (n = 30)				Onion peel extract (n = 31)
	Baseline	12 Weeks	Change	P ^a	Baseline	12 Weeks	Change	P ^a	P ^b
C18:1n9 (%)	13.5 ± 0.9	13.6 ± 0.9	0.1 ± 0.4	.122	14.0 ± 0.9	14.4 ± 2.7	0.4 ± 2.4	.334	.509
C18:2n6 (%)	10.8 ± 1.3	10.6 ± 1.2	−0.2 ± 1.0	.211	10.8 ± 1.3	10.2 ± 1.3	−0.6 ± 1.1	.007	.213
C18:3n6 (%)	0.1 ± 0.1	0.1 ± 0.1	−0.0 ± 0.1	.400	0.1 ± 0.1	0.1 ± 0.1	−0.0 ± 0.1	.194	.122
C18:3n3 (%)	0.2 ± 0.1	0.2 ± 0.1	−0.0 ± 0.1	.701	0.2 ± 0.1	0.2 ± 0.2	−0.0 ± 0.2	.746	.535
C20:4n6 (%)	15.0 ± 1.4	15.1 ± 1.3	0.1 ± 0.9	.118	14.8 ± 1.7	14.6 ± 1.9	−0.2 ± 1.1	.279	.276
C20:5n3 (%)	1.5 ± 0.7	1.4 ± 0.6	−0.1 ± 0.4	.016	1.4 ± 0.7	1.4 ± 0.6	−0.0 ± 0.6	.824	.258
C22:6n3 (%)	8.4 ± 1.0	8.2 ± 1.1	−0.3 ± 0.6	.824	7.8 ± 1.1	7.8 ± 1.6	−0.0 ± 1.0	.931	.239
SAT (%)	40.8 ± 0.7	40.8 ± 0.9	−0.0 ± 1.2	.255	41.6 ± 2.6	41.1 ± 1.5	−0.5 ± 3.0	.315	.308
PUFA (%)	43.8 ± 1.1	43.4 ± 1.2	−0.4 ± 1.1	.057	42.6 ± 3.0	42.1 ± 3.5	−0.5 ± 1.9	.199	.895
MONO (%)	14.4 ± 0.9	14.5 ± 1.0	−0.1 ± 0.5	.022	14.9 ± 0.9	15.4 ± 2.9	0.5 ± 2.6	.314	.446
PUFA n-3 (%)	13.1 ± 1.8	12.6 ± 1.9	−0.5 ± 1.1	.734	12.0 ± 1.9	12.2 ± 2.1	0.1 ± 1.1	.607	.043
PUFA n-6 (%)	30.7 ± 2.2	30.8 ± 2.2	0.1 ± 1.4	.071	30.5 ± 2.8	30.0 ± 3.0	−0.6 ± 1.4	.035	.075
n-6/n-3	2.4 ± 0.5	2.5 ± 0.5	0.1 ± 0.3	.529	2.6 ± 0.5	2.5 ± 0.5	−0.1 ± 0.3	.338	.048

Values are mean ± standard deviation.

P-values within group were statistically analyzed by paired t-test.

P-values between groups were statistically analyzed by t-test.

C18:1n9, oleic acid; C18:2n6, linoleic acid; C18:3n6, gamma-linolenic acid; C18:3n3, alpha- linolenic acid; C20:4n6, arachidonic acid; C20:5n3, eicosapentaenoic acid; C22:6n3, docosahexaenoic acid; MONO, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; PUFA n-3, omega-3 polyunsaturated fatty acid; PUFA n-6, omega-6 polyunsaturated fatty acid; SAT, saturated fatty acid.

Correlation between the changes of PUFAs and fat distribution

The correlation between the differences in PUFAs and fat mass percentage are listed in Table 3. The changes in arm fat percentage (ARFATP, P = .006), trunk fat percentage (TRFATP, P = .043), and total fat percentage (FATP, P = .017) were negatively correlated with the change of PUFA n-3 (Fig. 1), but were not significantly correlated with n-6/n-3. In addition, DHA was also significantly negatively correlated with ARFATP and FATP (P = .009 and .036, respectively). As the fat mass increases, EPA tended to decrease, but were not significantly correlated. Leg fat percentage was not correlated with erythrocyte FAs.

FIG. 1.

The change of PUFA n-3 negative correlated with (A) the change of ARFATP, (B) the change of TRFATP, and (C) the change of FATP. ARFATP, arm fat percentage; FATP, total fat percentage; PUFA, polyunsaturated fatty acid; TRFATP, trunk fat percentage.

Table 3.

Simple Correlation Coefficients (r) Among the Change of Polyunsaturated Fatty Acids and Fat Mass Percentage

	C20:5n3	C22:6n3	PUFA	PUFA n-3	n-6/n-3
ARFATP	0.076	−0.330^**	−0.348^**	−0.284^*	0.163
LEFATP	−0.176	0.019	0.087	−0.059	0.102
TRFATP	−0.016	−0.237	−0.378^**	−0.260^*	0.116
AndFATP	0.064	−0.191	−0.338^**	−0.158	0.035
FATP	−0.051	−0.268^*	−0.416^**	−0.304^*	−0.212

P < .05 and ^** P < .01.

AndFATP, android fat percentage; ARFATP, arm fat percentage; FATP, total fat percentage; LEFATP, leg fat percentage; TRFATP, trunk fat percentage.

Discussion

Obesity has become a major public health problem worldwide and has led to increased risk of major health diseases, such as coronary heart disease, several cancers, DM, hypertension, and metabolic syndrome.^2,3 We investigated the beneficial effects of chronic consumption of OPE on obesity and metabolic risk in Korean overweight and obese subjects. The placebo and OPE groups provided either capsules containing dextrin only (placebo group) or the encapsulated OPE twice per day for 12 weeks. Consumption of OPE for 12 weeks significantly affected body weight, BMI, BFM, and PBFM, compared with the baseline. Furthermore, OPE ameliorated the decrease in PUFA n-3 and increase in PUFA n-6, resulting in the prevention of increased n-6/n-3 ratio. In addition, the significant difference of PUFAs was negatively correlated with multiple fat regions.

After 12 weeks of taking OPE, subjects showed significant decreases in body weight, BMI, and PBFM. Moon et al. ¹⁵ reported that OPE (0.72% containing) has antiobesity effects by downregulating peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT enhancer-binding protein-α (C/EBP-α), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC); upregulating carnitine palmitoyltransferase-1α (CPT-1α); and uncoupling protein-1 (UCP-1) in adipose tissue of high-fat-fed rats. Onion peel tea also inhibited the increase in body weight and level of epididymal fat tissue. It also significantly reduced the total serum cholesterol, glucose, and leptin in high-fat diet-induced obese mice.²³

LA and ALA are essential FAs that must be obtained from diet and cannot be synthesized by humans because of a lack of enzymes necessary to insert a cis double bond at the n-6 or n-3 position of an FA.²⁴ There is competition between n-3 and n-6 PUFAs for the desaturation process because desaturation enzyme prefers ALA over LA. High intakes of LA and trans FAs interfered with the conversion of ALA into DHA and EPA.²⁵ Previous studies showed that plasma PUFA n-3 were negatively correlated with BMI and waist and hip circumference in human subjects.²⁶ The imbalance of n-6/n-3 FAs induced the increase of adipogenesis and proinflammatory cytokine. Excess n-6 FAs activate the cAMP protein kinase A, leading to the proliferation and differentiation of white adipose tissue and inhibition of PPAR-γ and UCP-1 target genes in relation to brown adipose tissue differentiation. As a result, high PUFA n-6 leads to increasing TG, insulin, and leptin resistance; decreased adiponectin levels; and FA oxidation.²⁵ Therefore, maintaining a balanced n-6/n-3 FAs (1:1–5:1) is important for health and prevention of obesity and associated diseases.

Many studies have reported that consumption of PUFA n-3s were associated with low incidence of various diseases.^27
–29 Chronic consumption of PUFA n-3 has reportedly decreased the risk of CVDs by reducing TG, ventricular fibrillation markers, inflammation, and endothelial dysfunction, resulting in improved blood circulation and blood pressure.²⁸ Supplementation with PUFA n-3 (EPA+DHA, ratio 2:1) is useful for improving insulin sensitivity. In addition, the supplementation significantly lowered levels of all inflammatory markers, such as tumor necrosis factor-α, interleukin-6, high sensitivity C-reactive protein, and ferritin.²⁹

Studies on polyphenol modulation of FA composition in the body are limited. A few studies suggest that flavonoids, and specifically anthocyanins and anthocyanin-rich juice, may increase EPA and DHA levels in the plasma through a PPARα-dependent mechanism.^30,31 Consumption of whole rye (WR) polyphenol (8 weeks) increased EPA and DHA in the plasma and liver of normal diet-fed rats.³² That study suggests that the consumption of WR, containing several polyphenols such as lignans and phenolic acids, modulated the microbiota composition inducing a stimulation of n-3 long-chain fatty acid synthesis.³¹ Burak et al. ³³ reported that metabolically healthy subjects who took 3.3 g/day ALA with either 190 mg/day quercetin (ALA+quercetin) or placebo (ALA+placebo) for 8 weeks did not affect quercetin in the plasma and erythrocytes. This result was considered due to nonconsumption of several polyphenol, but consumption of single flavonol.

A grape polyphenol extract has been shown to decrease FA transport and lipid accumulation, and increase glucose uptake and phospholipids n-3 PUFA levels in skeletal muscle of rats fed high-fat high-sucrose diets.³⁴ Consumption of green leafy vegetables with 25:1 n-6/n-3 FA ratio diet in spontaneously hypertensive rats also decreased the n-6/n-3 ratio and saturated FA in the erythrocyte membrane after 6 weeks.³⁵ Ponder et al. ³⁶ study reported that erythrocyte DHA increased by 20% when the LA:ALA ratio was decreased. Thus, consumption of enriched TP could contribute to amelioration of the erythrocyte FA composition by improving FA transport pathway and n-6/n-3 FA ratio.

In this study, OPE prevented the decrease in PUFA n-3 and increase in PUFA n-6, resulting in the prevention of increased n-6/n-3 ratio. Furthermore, elevated erythrocyte PUFA n-3 are associated with reduction of ARFATP, TRFATP, and FATP resulting in metabolic disorders. Therefore, improvement of erythrocyte FA composition leads to increased lipid oxidation and decreased fat accumulation in multiple fat regions. Consequentially, OPE effectively alleviated adiposity and reduced BFM and body weight in overweight and obese subjects. This effect was considered to be the result of taking the whole extract of onion peel, not the single polyphenol extracted from the onion peel.

However, this study has some limitations. Desaturation enzymes (fat desaturase 1 and 2) were not studied. Therefore, how OPE helps maintain DHA and EPA levels has not been precisely investigated. Additionally, lipid beta-oxidation and fat accumulation enzymes were not included in this study. We suggest that further studies should be conducted to investigate the mechanism of OPE dose-dependent supplementation in overweight and obese subjects.

In conclusion, OPE effectively prevented the increase of n-6/n-3 FA ratio in overweight and obese subjects. As the PUFA n-3 change in erythrocytes increased, corresponding decreases in fat accumulation were observed. Therefore, OPE may be beneficial for preventing or reversing obesity.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2016R1D1A1B03935660).

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