Can daily consumption of enriched fatty acids diet be effective in improving metabolic syndrome? An attractive paradox for walnut kernel

Abstract Imagine consuming a daily diet rich in fatty acids to help treat diseases such as hypertension and obesity. This concept presents an attractive paradox. In particular, consuming walnut kernels is beneficial for treating diseases associated with metabolic syndrome (MetS), including type 2 diabetes, cardiovascular disease, dyslipidemia, and obesity. Different parts of the Juglans regia tree (family Juglandaceae), including its leaves, green husks, bark, and septum, have shown promising effects on pathological conditions related to MetS. The therapeutic advantages of consuming walnut kernels for MetS can be attributed to the presence of polyunsaturated fatty acids and polyphenolic compounds such as juglone and ellagic acid. Diets enriched with walnut kernel have a positive impact on MetS complications by reducing diastolic blood pressure, improving blood lipid profiles, lowering fasting blood sugar levels, and increasing insulin sensitivity. The potential cellular mechanisms responsible for these benefits involve activating the cholesterol hemostasis pathway by inhibiting sterol regulatory element‐binding proteins (SREBPs), proprotein convertase subtilisin/kexin type 9 (PCSK9), and cholesteryl ester transfer protein (CETP). Furthermore, other by‐products of walnuts, such as leaves and green husks, have also demonstrated effectiveness in managing MetS. These findings highlight the potential of incorporating walnut‐based products into our diets as a natural approach to combating MetS and its complications.

A walnut is an edible nut from the Juglans regia tree (family Juglandaceae).The various parts of J. regia such as green husks, bark, leaves, and shells are also used in traditional medicine and the pharmaceutical industry (Almonte-Flores et al., 2015;Boulfia et al., 2021).
Furthermore, polyphenols such as vanillic acid, t-ferulic acid, myricetin acid, ellagic acid, and coumaric acid have been extracted from green husk (Hosseini, Huseini, et al., 2014;Hosseini, Jamshidi, et al., 2014;Wang et al., 2019).Secondary metabolites from various parts of J. regia are summarized in Figure 1.In this article, we have studied the effects of walnuts in treating metabolic syndrome and related risk factors.
It seems that most research has emphasized on the nutritional value of walnut kernels in reducing the risk of MetS, while the potential effects of other parts of J. regia on MetS have not been extensively studied.Various parts of the plant, including the kernel, leaf extract, green husk extract, kernel and septum extract, and even the bark of the tree, are effective in treating complications associated with metabolic syndrome.Different studies have highlighted the promising biological effects of different parts of J. regia on pathological conditions related to metabolic syndrome, as summarized in Figure 2.

| C ARDIOVA SCUL AR DIS E A S E
Cardiovascular diseases (CVD) are a general medical term that encompasses all diseases of the blood circulatory system, including congenital heart defects (CHD), heart failure (HF), hypertension (HTN), and stroke.HTN is a medical condition that is considered a major risk factor for cardiovascular diseases (Tsao et al., 2022).
Atherosclerosis is a serious condition where arteries become thickened or hardened with fatty plaques and is associated with stroke, coronary artery disease, and peripheral vascular disease (Daugherty et al., 2017).According to studies, natural products play a critical role in the prevention and treatment of cardiovascular disorders (Hernández et al., 2023;Shukla et al., 2010).
The biological effects of walnut kernels on cardiovascular diseases, especially atherosclerosis are summarized in Table 1.

| Clinical studies
Several clinical studies have been conducted to investigate the effect of consuming walnut kernels on reducing the risk of cardiovascular diseases.In these studies, the blood pressure of walnut consumers has been compared to non-consumers.Although walnut consumption demonstrates the effects on blood pressure and heart rate, these effects were not found to be significant in many cases.
On the other hand, recent studies have shown that replacing polyunsaturated fatty acids (n-6 PUFA or trans fatty acids) with n-3 PUFA (α-linolenic acid [ALA]) in dietary intake improves cardiovascular health.Therefore, consuming walnuts as a source of n-3 PUFA could be considered a promising approach to reducing the occurrence of CVD (Tsao et al., 2022).Furthermore, Tindall and coworkers in a randomized controlled trial with 45 individuals demonstrated that replacing saturated fat with walnuts (57-99 g/day) or a-linolenic acid, improved central diastolic blood pressure in adults at risk for cardiovascular disease (p = .04).This effect is not substantial but it seems that a small change in dietary diet patterns could be effective in the prevention of CVD (Tindall, McLimans, et al., 2019).
In addition, Guasch-Ferré et al. (2021) demonstrated that walnut consumption and plasma metabolites such as lipids, amino acids, purines, and acylcarnitines could decrease the risk of CVD in the Mediterranean population.Overall, there was a lack of evidence suggesting that increasing long-chain omega-3 or alpha-linolenic acid had any impact on serious adverse events, adiposity, or lipids.However, it was observed that long-chain omega-3 did have a slight effect in reducing triglycerides and increasing HDL levels (Abdelhamid et al., 2020).
In another study, a walnut diet led to a reduction in SBP (approximately 6 mmHg reduction, p = .034)and improved blood pressure regulation in elderly individuals with mild hypertension (Domenech et al., 2019).
In an observational study involving 3341 participants, coronary artery risks were compared between walnut consumers and nonwalnut consumers.It was found that the quality of the diet was higher in walnut consumers.Furthermore, daily walnut ingestion resulted in a significant reduction in DBP and heart rate (p = .09),but it did not affect systolic function (Steffen et al., 2021).
A large elderly cohort study conducted over 2 years with 708 participants showed that daily walnut consumption had no effect on MetS and its complications, and even the reduction in SBP was not significant (Al Abdrabalnabi et al., 2020).
Furthermore, another randomized controlled study with 112 participants revealed that a walnut-enriched diet (56 g) for 6 months had no significant effect on blood pressure but could improve endothelial function (Njike et al., 2015).

| Effect on endothelial function
In a clinical study involving overweight adults, a daily intake of walnuts (56 g) improved endothelial function and significantly increased flow-mediated dilation (p = .019)without significant weight change F I G U R E 1 Secondary metabolites from the different parts of Juglans regia.(Katz et al., 2012).Furthermore, in a randomized controlled crossover trial, a walnut-enriched diet (56 g/day) in 24 diabetic patients (mean age 58 years) significantly improved endothelium-dependent vasodilatation with flow-mediated dilation (FMD) increased by 25% (p = .04)(Ma et al., 2010).
In another randomized crossover study, it was determined that the addition of walnut (40 g) or olive oil (25 g) acutely improved FMD and endothelial function in hypercholesterolemic patients (Cortés et al., 2006).The polyunsaturated fatty acids (PUFA) present in walnuts decreased DBS, increased FMD (+34%), and improved cardiovascular responses to stress compared to the average American diet (West et al., 2010).

| Mechanism of protection in CVD
An in vivo study on isoproterenol-induced myocardial infarction revealed that walnut kernels have protective effects on MI rats, by decreasing hydroperoxide and thiobarbituric acid reactive substances (TBARS) levels in the heart compared with ISO-control rats (p < .05).
Another study carried out in rats showed the normalization of hypertension by balancing the redox system and the production of NO (Joukar et al., 2017).
The predicted mechanisms for the therapeutic effect of walnut consumption on CVD risk reduction may be associated with a reduction in endothelin-1 mRNA in the aorta and cholesterol ester concentration in the aorta (Davis et al., 2006).Nergiz-Ünal et al. (2013) also reported a 55% reduction in the progression of atherosclerotic plaques in the aortic arch by reducing lipid and prothrombin accumulation.
Overall, research suggests that consuming walnuts may have promising effects in reducing the risk of cardiovascular disease.The majority of research has focused on the impact of a walnut-enriched diet concerning CVD, while the potential effects of other parts of J. regia on CVD have not been extensively studied.However, it is still unclear whether these benefits are related to PUFA or secondary metabolite.
Generally, there have been conflicting results from randomized trials regarding the effect of a walnut kernel-enrich diet on CVD.While some studies have shown that walnut-enriched diets (56 g/day) can significantly lower diastolic blood pressure (about 2-3 mmHg reduction), a cohort study found no significant effect on blood pressure in F I G U R E 2 Biological effects of different parts of Juglans regia on pathological conditions related to metabolic syndrome.

TA B L E 1
The biological effects of the walnut kernel on cardiovascular disease.

| HYPERLIPIDEMIA
Dyslipidemia is a disease in which the lipid profile changes when the total cholesterol is ≥240 mg/dL or HDL-C is <40 or the LDL-C is ≥130.
One of the major risk factors for the progression of atherosclerosis is cholesterol.Based on U.S. healthcare data, hyperlipidemia was the 35th most expensive disease in 2016 (Tsao et al., 2022).The biological effects of walnut consumption on dyslipidemia are summarized in Table 2.

| Effects of walnut kernel enriched diet on hyperlipidemia
In a clinical study with 9660 participants, Askari et al. (2013) demonstrated that frequent consumption of edible nuts (pistachios, walnuts, hazelnuts, and almonds) particularly ≥4 times a week was significantly associated with a lowering in the level of total cholesterol, triglycerides, LDL-c, and apo lipoprotein B/apo lipoprotein A ratios (p < .05).
In the Korean randomized, controlled crossover study involving 84 patients with MetS, it was observed that daily consumption of walnuts (45 g) for 16 weeks could increase HDL-C (p = .028)(Hwang et al., 2019).In another clinical study with 245 participants, significant changes in lipid profile were observed.In this study, the level of HDL was increased in comparison to a low-fat diet group (p = .05)and a lowcarbohydrate diet group (p < .01)(Le et al., 2016).The consumption of a walnuts enriched diet (30 g/day) by 58 patients caused a significant increase in HDL to total cholesterol ratio (p = .049)and HDL levels (p = .046).Additionally, there was a 10% decrease in LDL-C levels (Tapsell et al., 2004).In another clinical study with 49 patients, walnut consumption significantly reduced total cholesterol (4.1%), LDL (5.9%), and lipoprotein levels (6.2%) (Zambón et al., 2000).
A clinical study by Kalgaonkar et al. (2011)

| Mechanism of anti-hyperlipidemic activity
Another study in participants with polygenic hypercholesterolemia concluded that the mechanism of LDL-c reduction was a 50% increase in LDL-c uptake by HepG2 cells (Muñoz et al., 2001).
An in vivo study conducted in rats with streptozotocin-induced gestational diabetes supported the reduction of the unusual lipid profile by walnut consumption via suppression of relative mRNA expression of sterol regulatory element-binding transcription factor 1, acetyl-coenzyme A, carboxylase fatty acid synthase, and stearoyl-CoA desaturase 1 (Sun et al., 2020).Another study denotes a 36% reduction in total cholesterol and a 23% reduction in triglyceride compared to the control group (Nergiz-Ünal et al., 2013).
"In participants with polygenic hypercholesterolemia, another study concluded that the mechanism of LDL-c reduction was a 50% increase in LDL-c uptake by HepG2 cells (Muñoz et al., 2001).An in vivo study conducted in rats with streptozotocin-induced gestational diabetes supported the reduction an abnormal lipid profile by walnut consumption, achieved through the suppression of relative mRNA expression of sterol regulatory element-binding transcription factor 1, acetyl-coenzyme A, carboxylase fatty acid synthase, and stearoyl-CoA desaturase 1 (Sun et al., 2020).Another study denotes a 36% reduction in total cholesterol and a 23% reduction in triglycerides compared to the control group (Nergiz-Ünal et al., 2013)." An in vivo study with walnut kernels in isoproterenol-induced myocardial infarction showed the normalization of myocardial tissue lipids (Sun et al., 2019).Additionally, the consumption of kernel extract indicated a significant decrease in triglycerides and an increase in the expression of hepatic peroxisome proliferator-activated receptor alpha (PPAR α) and acyl-COA oxidase 1 (ACOX 1 ) (Shimoda et al., 2009).
According to literature, daily walnut kernel consumption can decrease the levels of total cholesterol, LDL, and triglycerides while increasing the level of HDL.The possible mechanism of these effects is the suppression of relative mRNA expression of SREBPs and an increase in the expression of PPAR α ACOX 1 .

| DIABE TE S
Diabetes is a group of diseases that disrupt glucose regulation (Tsao et al., 2022).According to the WHO report, the number of diabetic people has increased from 108 million in 1980 to 422 million in 2014, with a higher prevalence in low-and middle-income countries.In the United States alone, diabetes was the leading cause of death for 87,647 people in 2019 (Tsao et al., 2022).The biological effects of walnut consumption on diabetes are summarized in Table 3.

| Clinical studies
A clinical study of 34,121 participants conducted by Arab et al. (2018) found that walnut consumption reduced the relative risk of diabetes by 68% compared to non-walnut consumers.Another study involving 1833 participants demonstrated that walnuts can significantly reduce the risk of diabetes in the CVD population (p = .02)(Guasch-Ferré et al., 2021).Additionally, a clinical study on walnut consumption showed a greater decrease in fasting insulin levels compared to the control group (p = .046)(Tapsell et al., 2009).Kalgaonkar et al. (2011) reported a significant reduction of HbA1C compared to the control group (p = .0006).
Similarly, clinical studies involving walnut kernels revealed a significant decrease in fasting blood glucose levels and HbA1c compared to the control group (p = .013,p = .021)(Hwang et al., 2019).
A randomized controlled study with 112 participants revealed that a walnut-enriched diet (56 g) had no significant effect on BP but could improve the blood glucose level (Njike et al., 2015).
Furthermore, another randomized clinical trial with 24 individuals demonstrated that a walnut-enriched diet had not significant effect on insulin sensitivity (Ma et al., 2010).

| Mechanism of anti-diabetic activity
A study on walnut consumption in rats with gestational diabetes showed a decrease in FBG, gestational diabetes mellitus, and an increase in insulin and hepatic glycogen (Sun et al., 2020).
Based on previous studies, daily consumption of walnutsenriched dairy products could decrease FBS and HbA1c levels while increasing insulin levels and insulin response.

| BODY WEI G HT
According to the latest guidelines, obesity is defined as a waist circumference ≥35 inches (88 cm) in women and ≥40 inches (102 cm) in men.Due to lifestyle changes, the prevalence of obesity in individuals aged 20 and older is now 39.9% in men and 41.1% in women.Studies indicate that overweighting is an important risk factor for CVD and increases the risk of MetS complications such as hypertension, diabetes, and dyslipidemia (Tsao et al., 2022).
Walnut kernel administration in aging mice could significantly decrease body weight and modulate antioxidant enzyme activity (Liu et al., 2019).Therefore, the management of obesity is crucial, and one approach involves the use of anti-obesity medications; however, it's important to note that these medications may cause side effects (Hosseini & Hosseinzadeh, 2015).The biological effects of walnut consumption on body weight are summarized in Table 4.  and BMI (Le et al., 2016).In another study with 100 participants, a walnut-enriched reduced-energy diet led to a significant 8.9% reduction in body weight (Rock et al., 2017).
Nijke and coworkers represented that daily consumption of walnuts had no significant effects on anthropometric measures in a clinical study involving 112 participants (Njike et al., 2015).Additionally, some studies have suggested that daily walnut consumption may lead to weight gain, although the increase was not found to be significant (Sabaté et al., 2005).In another randomized parallel trial conducted over 2 years on healthy elderly individuals, daily consumption of walnuts (28-56 g/day) did not show a significant impact on body weight or body fat (Bitok et al., 2018).
According to studies, daily consumption of walnut kernels appears to have conflicting effects on body weight.It seems that consuming walnut kernels has no significant impact on increasing or decreasing body weight.However, due to the promising effects of walnut consumption on other complications of MetS, walnuts can be added to a diet without concern about the negative effects on BMI or body weight.
Ultimately, the therapeutic effects of consuming walnut kernels on MetS complications, including the reduction of heart rate, diastolic and systolic blood pressure, total lipid profile, diabetic complications, and body weight, are illustrated in Figure 3.

| EFFEC TS OF OTHER PARTS OF J. REG IA ON ME TS
In addition to the walnut kernel, other parts of J. regia such as leaves, green husk, septum, and hull have a desirable biological effect that is attributed to high amounts of phenolic compounds with potential antioxidant effects.Some of the phenolic compounds found in walnuts include juglone, ferulic acid, vanillic acid, ellagic acid, chlorogenic acid, and coumaric acid (Ebrahimi et al., 2017).The effect of these parts of J. regia on MetS was summarized in Table 5.

| Walnut leaves
The walnut leaves are also used in traditional medicine.The extract of walnut leaves has shown important biological effects due to secondary metabolites, especially phenolic compounds including flavonoids and naphthoquinones (Hosseinzadeh et al., 2011).
Walnut leaves are a valuable source of polyphenolic compounds such as hydroquinone, 4-hydroxybenzoic acid, quercetin derivatives, and caffeic acid.The extract of walnut has a high antioxidant capacity and may be introduced for the treatment of inflammatory-related diseases (Altemimi et al., 2023).
In a study by Mollica et al. (2017), walnut leaf powder in streptozotocin-induced diabetic rats indicated a relapse of hypercholesterolemia.
Nasiry, Khalatbary, and Ahmadvand (2017) and Nasiry, Khalatbary, Ahmadvand, et al. (2017) reported in an in vivo study that walnut leaf extract significantly reduced the FBS (p < .001).In vitro studies have demonstrated the inhibition of α-glucosidase and α-amylase by walnut leaf extract (Mollica et al., 2017;Rahimzadeh et al., 2014).Pitschmann et al. (2014) demonstrated the increase in glucose uptake and PTP1B inhibitory effect of walnut leaves.Overall, it appears that the oral consumption of walnut leaf extract may effectively control blood glucose levels and serve as a promising treatment for diabetes through various mechanisms, including αamylase inhibition, increased glucose uptake, and PTP1B inhibition.

| Walnut septum
The walnut septum, the wooden membrane that separates the two halves of the walnut kernel, has demonstrated important biological effects both in vivo and in vitro, particularly in the treatment of diabetes.In a study on streptozotocin-induced diabetic rats, the extract from the walnut septum reduced oxidative stress and inflammation (Zhang et al., 2022).Another study exploring the benefits of both walnut kernels and the septum in a D-galactose-induced aging model and naturally aged rats indicated potential hypoglycemic effects of the septum (Mateș et al., 2023).
According to the literature, the antioxidant and anti-inflammatory effects of walnut septum are related to phenolic compounds.These compounds interrupt the lipid peroxidation cycle and modulate the signaling pathways including PI3K/Akt/mTOR, Nrf2/EpRE, and NF-kB (Mateș et al., 2023).

| Walnut green husk
Another walnut by-product is the green husk that covers the shell of mature walnut fruits.Despite being considered a waste product, this part of walnuts is used as an herbal medicine because of the presence of biological compounds.
An in vivo study conducted in diabetic rats supports the beneficial effects of the walnut green husk on increasing B-cell count and insulin levels (Javidanpour et al., 2012).
Interestingly, different parts of the walnut yield distinct results.Walnut green husks have been shown to prevent abnormal weight gain by modulating lipid homeostasis (Wang et al., 2021) and reducing the body weight, fat accumulation, and hypertrophy of adipose tissue in cases of obesity due to high-fat diet (Wang et al., 2019).

| CON CLUS ION
To address the prevalence of MetS, it is crucial to identify effective Clinical studies have not shown a significant effect on vessel stiffness, but several studies have demonstrated the therapeutic effects of a walnut-enriched diet on endothelial function.Based on in vitro and in vivo studies, potential mechanisms for protection from CVD include antioxidant activity, regulation of NO production, and a reduction in endothelin-1 mRNA expression.
studies A randomized, crossover, placebo-controlled study involving 25 volunteers demonstrated that consuming meat products with walnuts significantly reduced body weight compared to baseline measurements (Olmedilla-Alonso et al., 2008).Additionally, the 1-year behavioral weight loss intervention involving 245 overweight women with a walnut-enriched diet resulted in reductions in body weight TA B L E 3 Walnut consumption effects on diabetes.
Mohammadi et al. (2012) suggested the walnut leaf has more vital antiglycation ability in diabetic test rats after consumption of 28 μg/mL walnut leaf extract.Another in vivo study byJelodar et al. (2007) reported a significant increase in normal B cells, granular B cells, and Langerhans cells density upon consumption of walnut leaves.
solutions with minimal adverse effects.This review article aims to explore the impact of J. regia on MetS.While many studies have emphasized investigating the potential benefits of consuming walnut kernels in reducing the risk of MetS, limited research has occurred on exploring the effects of other components of J. regia on MetS.Despite numerous studies on the impact of consuming walnut kernels on MetS, it remains unclear whether these benefits are due to PUFA or secondary metabolites.Randomized trials have produced conflicting results regarding the effect of a diet enriched with walnut kernels on MetS.Overall, walnut kernels are edible nuts that are commonly included in daily diets.Numerous studies have shown that consuming walnuts and a diet enriched with n-6 PUFA and n-3 PUFA can have positive effects on MetS.It appears that walnut kernel activates the cholesterol hemostasis pathway through SREBPs, PCSK9, and CETP.Additionally, modifications in insulin signaling pathways through protein tyrosine phosphatase 1B (PTP1B), inhibition of inflammatory response, and oxidative stress lead to a decrease in MetS complications.Figure4summarizes the pathways involved in the therapeutic effect of the walnut kernel on metabolic syndrome.In conclusion, a diet enriched with walnut kernels can help monitor complications associated with MetS by reducing diastolic blood pressure, improving blood lipid profiles, lowering FBS levels, and increasing insulin sensitivity.Additionally, other by-products of walnuts such as leaves and green husks have also shown to be effective in managing MetS.Walnut leaf extract has been found to have a potent antidiabetic effect through various mechanisms.Meanwhile, the green husk of walnuts has been shown to aid in weight loss and F I G U R E 3 Different anti-metabolic syndrome effects of the walnut kernel.TA B L E 5The effect of other parts of Juglans regia on MetS.

Design of study Part of plant Dose Finding Reference
Walnut consumption effects on hyperlipidemia.
Walnut consumption effects on body weight.