Beneficial Effects of Fennel (Foeniculum Vulgare) in Treating Obesity in Rats

The most common complications involve alterations in metabolic function that are risk factors for cardiovascular disease, namely hyperglycemia, hyper-insulinemia, and glucose intolerance, liver fat accumulation, dyslipidemia (increased serum triglyceride and decreased serum HDL-cholesterol concentrations; a predominance of smaller LDL particles and an increased number of large VLDL particles), and endothelial dysfunction ¹. Fat accumulation in non-adipose tissues such as in the liver, skeletal muscles, heart appears to be a key feature distinguishing metabolically healthy from metabolically abnormal subjects. Obesity has deleterious effects on metabolic homeostasis, and affects numerous body organs ^{2, 3}. Lipids are essential for membrane synthesis, maintenance of membrane integrity, as an energy source, as hormone precursors, and as signaling molecules. Hyperlipidemia is usually characterized by elevated serum total cholesterol and decrease in High density lipoprotein (HDL) cholesterol and increase in Low density lipoprotein (LDL) cholesterols. It is observed that there is also an association between hyperlipidemia, and serum triglycerides ⁴. In the presence of severe hypertriglyceridemia or mixed hyperlipidemia, the combination of statins and fibrates is a possible treatment ⁵. Fennel is an aromatic herb belonging to the Parsley family. It is used as a spice and possesses a sweet taste that is similar to anise. Fennel seed shape is oval and has a strong scent, while the fruit have a slightly sweet and slightly spicy. Sweet fennel oil is made up predominantly of anethole (50 to 80%), fenchone, and estragole. The seeds also contain fiber and complex carbohydrates ⁶.

Experimental animals and treatment: Adult male Albino rats weighing 150–160gm were obtained from the animal house of the Faculty agriculture, Alexandria University, Egypt. They were housed in a clean and well ventilated animal house with a constant 12 hr light and 12 hr dark schedule. They lived in five different groups (seven animals per group) at 25-27^oC.The animals were provided with standard diet and tap water was supplied. They were acclimatized under laboratory conditions for one week before the experiment. Diets; Composition of the experimental diet (g/kg diet) was according to the formula of ⁷. It is including the normal diet for the control rats (fat 5%, carbohydrates 65%, proteins 20.3%, fiber 5%, salt mixture 3.7% and vitamin mixture 1%). The high fat diet contained fat 46%, carbohydrates 24%, proteins 20.3%, fiber5%, salt mixture 3.7% and vitamin mixture 1%.Normal and HFD; high fat diet constituents were purchased from El-Gomhoria Company, Cairo, Egypt. HFD was preserved at 4^oC until being used. Atorvastatin was obtained from local pharmacies, Cairo, Egypt and ground using a mortar. The drugs were administered orally once a day. Fennel (Foeniculum vulgare) seeds were obtained and dried fennel seeds (Shamar) were washed with tap water to remove possible potential dust. Afterwards, it was dried by cotton cloth to remove the excess liquid prior to drying. Drying was achieved at room temperature for 48 hr. Then a grinder mill and sieves were used to obtain a powder particle size of less than 0.2mm ⁸.

Experimental design: Thirty five Male Albino rats were randomly divided into five groups; (7 rats/ group) as follows: Group 1: (control group): Animals of this group were fed normal diet. Group 2: (obese group): rats of this group were fed high fat diet for two weeks. It is including the normal diet for control rats (fat 5%, carbohydrates 65%, proteins 20.3%, fiber 5%, salt mixture 3.7% and vitamin mixture 1%). The high fat diet contained fat 46%, carbohydrates 24%, proteins 20.3%, fiber 5%, salt mixture 3.7% and vitamin mixture 1%.Normal and HFD constituents were purchased from El-Gomhoria Company, Egypt. HFD was preserved at 4oC until used. Group 3: (obese rats treated with fennel): Animals of this group were fed high fat diet; HFD for two weeks then treated with the fennel herb fennel 300 mg/kg body weight. Group 4: (obese rats treated with atorvastatin drug): rats of this group were received high fat diet two weeks then treated with the atorvastatin drug 10 mg/kg ⁹. Group 5: (obese rats treated with atorvastatin drug and fennel herb): rats of this group were received high fat diet for two weeks then treated with atorvastatin drug and fennel herb.

The rats received a high fat diet contained containing fat 46%, carbohydrates 24%, proteins 20.3%, fiber 5%, salt mixture 3.7% and vitamin mixture 1%. Normal and HFD constituents were purchased from El-Gomhoria Company, Egypt. HFD was preserved at 4^oC until used for two weeks. Treatment with fennel and atorvastatin drug started after two weeks. Studies of blood samples: For the determination of blood parameters, some of blood was collected into Ethylenediaminetetraacetic acid (EDTA) EDTA –treated tubes for determination hematological parameters as: Determination of serum total protein was done according to Gornall et al. ¹⁰. Determination of serum albumin was done according to Doumas et al.¹¹. Determination of serum total cholesterol was done according to Allain et al. ¹². Determination of serum triglycerides was done according to Fassati and Prencipe ¹³. Determination of serum high density lipoproteins (HDL) Cholesterol levels and Determination of serum low density lipoproteins (LDL) Cholesterol levels according to Fruchart ¹⁴. Determination of serum urea was done according to Fawcett and Soctt ¹⁵. Determination of serum creatinine was done according to Bartles et al.¹⁶. Determination of alanine aminotransferase(ALT) and Determination of aspartate aminotransferase activity (AST) according to Tietz ¹⁷. Determination of alkaline phosphatase (ALP) was done according to DGKC ¹⁸. Determination of lipid peroxide (Malondialdehyde) (MDA) was done according to Ohkawa et al. ¹⁹. Determination of Myeloperoxidase (MPO) was done according to Zhang et al.²⁰. Determination of Catalase (CAT) was done according to Aebi ²¹. Determination of Superoxide dismutase (SOD) was done according to Nishikimi et al.²². Determination of Glutathione peroxide (GPx) was done according to Paglia and Valentine ²³.

Obesity is caused by various environmental and genetic factors: one of the main environmental factors causing obesity is the intake of a HFD. In this study, high fat diet (HFD) caused significant increase in the body weight of the obesity animal, this result was in agreement with Galisteo et al.²⁵ observed that food intake in obese rats was significantly increased after 12 or 24 weeks. This means that the total energy intake was higher in obese rats than that in the lean control one. Consumption of high fat diet led to obesity and overweight because it facilitates the development of a positive energy balance leading to an increase in visceral fat deposition, this lead to abdominal obesity in particular ²⁶. Schrauwen-Hinderling et al.²⁷ found that high fat diet feeding is accompanied by molecular adaptation that favors fat storage in muscle rather than oxidation.

In this study the body weight of the group which treated with fennel herb significantly decreases, this results agree with Schone et al.²⁸ reported that food intake in rats treated with either one of the fennel extracts. In this respect, it can be proposed that trypsin inhibitors in fennel reduce food intake and stimulate cholecystokinin release, increasing satiety and that is the reason for fennel's association with weight control. Weight loss Fennel increases the metabolism of fats and sugars in liver and pancreas. It dissolves fat deposits in bloodstream also and allows it to be used as an energy source. These aspects combined with its natural diuretic effect and a reputation as an appetite suppressant makes it an excellent remedy for weight loss ²⁹. In the present study, fennel reduced the body weight gain. This may be due to several isoflavans constituents of fennel as phytoestrogens, which like estradiol, affect the serotonergic system, inhibiting serotonin re-uptake and thereby increasing the levels of serotonin in synaptic clefts, this enhances satiety and promote weight gain ³⁰.

In the current study the rats which treated with atorvastatin significantly decrease the body weight, this result was agreement with Erdmann et al.³¹ observed that the treatment of over-weight and obesity has been shown to reduce plasma cholesterol. In this study it was observed that combination of fennel and atorvastatin showed significant decrease in the body weight compared to other group and reach to the normal. In this study, high fat diet caused significant increase in the protein of the obese animal. In this study the protein of the group which treated with fennel herb significantly decreases. In current study, the rats which treated with atorvastatin significantly decrease the protein. In this study it was observed that combination of fennel and atorvastatin showed significant decrease in the protein compared to other group and reach to the normal. In the present study the high fat diet caused significant increase in the albumin of the obese animal. In this study the albumin of the group which treated with fennel herb significantly decreases. In current study, the rats which treated with atorvastatin significantly decrease the albumin.

In the present study, HFD caused significant decrease in platelet, this result was agree with Chen et al.³² reported that the effects of naturally-gained obesity on hematological and biochemical parameters are scarce. Chronic inflammation affects many hematological parameters, including erythrocytes, leukocytes and platelets. It is now well-established that obesity results in a state of chronic low-grade inflammation ³³. In the current study, the rats which treated with fennel herb showed increase in the platelet count, this result was in disagreement with Kaur ³⁴ who reported that Fennel seeds are also known to have anti-cancerous, antihirsutism, anti-inflammatory, antioxidant, anti-platelet, anti-thrombotic, and anti-spasmodic properties. Previous studies have shown that Fennel seeds contain high levels of nitrites and nitrates. Nitrites and Nitrates are known to play crucial roles in maintaining vascular and digestive functions.

The increased serum LDL level in obese rats has been also recorded in high fat diet supplemented rats ³⁵. This was explained by the decreased HDL level, as recorded in our study, thus decreasing the reverse cholesterol transport from the blood stream to the liver ³⁶. Different fennel extracts seeds used in the present study could reduce serum cholesterol level in obese rats. Non appreciable reduction in serum triglycerides level was recorded in obese rats treated with either one of fennel extracts seeds. In current study, the rats which treated with fennel significant decrease in serum cholesterol and LDL levels accompanied with insignificant decrease in serum triglycerides level. While, significant increase in serum HDL level, this result was agree with Choi and Hwang ⁶ who observed that fennel methanolic extract seeds treatment could significantly decrease serum LDL level and increase serum HDL level in obese rats. The other fennel extracts could insignificantly reduce LDL level and rise HDL level in obese rats. These results indicated that the constitution of fennel seeds plays an important role in improving blood lipid profile. This could be explained as fennel methanolic extract could significantly increase HDL level. This type of lipoprotein could stimulate the reverse cholesterol transport from the blood stream to the liver ³⁶. Furthermore, it has been shown that fennel, involved in herbal formulation, could delay upper gastrointestinal transit which promotes a decrease in fat and sugar absorption ³⁷.

In the present study treatment with atorvastatin significant decrease in serum cholesterol and LDL levels accompanied with insignificant decrease in serum triglycerides level. While, significant increase in serum HDL level In this study we observed that combination of fennel and atorvastatin showed more effecting compared to other group and reach to the normal. In the current study indicates that the HFD increase kidney funcation (blood urea, creatinine and uric acid), this results was in agreement with Abrass ³⁸ who reported that HF diet groups were associated with high serum cholesterol and triacylglycerol, in addition to histopathological alterations in kidneys. The role of HF as a prominent risk factor for renal disease progression has been increasingly recognized and deterioration of renal function also promote alterations in lipid metabolism. Lipid abnormalities are frequently associated with renal disease. Obese people are at increased risk for proteinuria and chronic kidney disease, independent of concurrent diabetes mellitus or hypertension.

Griffin et al. ³⁹ found that patients with obesity-related glomerulopathy (ORG), defined as glomerular disease in obese patients in the absence of other renal disease-associated conditions, develop proteinuria prior to the onset of azotemia ⁴⁰. In the current study indicates that fennel significant decrease creatinine and uric acid. The present results were in agreement with Fasset et al.⁴¹ who observed that atorvastatin 10 mg would significantly slow the rate of decline of kidney function with chronic kidney disease. In the present study , the obesity rats indicates the increase in the liver function this results was agree with Choi ⁴² who reported that elevated serum hepatic enzyme activities may be associated with a high prevalence of fatty liver, which is frequently observed in obese humans. In the present study, the rats which treated with fennel herb indicates significant decrease in the liver function this results was in agreement with Ozbek et al.⁴³ who observed that herbal drugs and essential oils of fennel have hepato-protective effects. In the present study, the rats which treated with atorvastatin indicates significant decrease in the liver function this results was agree with Ali et al.⁴⁴ who showed that oral atorvastatin is capable of improving liver function enzymes (ALT, AST, and ALP) and cause a significant decrement in their serum levels after induction of hypercholesterolemia in rats ^{45, 46, 47, 48, 49}. Previous studies illustrated that LPO and oxidative stress can severely elevated in patients with diabetes and hyperlipidemia ⁵⁰ and that atorvastatin can improve serum levels of liver enzymes by its antioxidant effect against the liver damage.

The current study indicates that the HFD increase in oxidative stress, these results are in agreement with Diniz et al.⁵⁰ who reported that oxidative stress was found to be associated with obesity. There is a growing awareness that obesity is a prime risk factor for the development of dyslipidemic profile and that oxidative stress may play a role in various adverse effects of obesity. The present data revealed that the lipid peroxidation product (MDA) recorded significant elevation in obese rats when compared with the lean control one. In the present study, the rats which treated with fennel herb indicate significant decrease in the oxidative stress, this result agreed with Choi and Hwang ⁶ who reported that the significant reduction in serum MDA level observed in obese rats treated with either one of the fennel extracts could be attributed to the anti-lipid per oxidative capacity of fennel constituents in its methanolic extract. Augmentation of the antioxidant defense system and the anti-lipid per oxidative activity of aqueous fennel extract has been reported ⁵¹.

The anti-inflammatory and antioxidant activities of fennel have been reported by Choi and Hwang ⁶. Anti-oxidant Fennel contains flavonoid anti-oxidants compounds like kaempferol and quercetin which helps eliminate harmful free radicals from the body, thus protecting from infection and aging. Fennel seeds are generally eaten for the taste but also very healthy owing to the nutrition value attached to it. Fennel is used for various health benefits that are derived from its anti-oxidants. In the present study, the rats which treated with atorvastatin indicates significant decrease in the oxidative stress, this results was agree with Koter et al.⁵² who reported that atorvastatin showed a significant reduction in the MDA level. Medicinal plants can be used in the treatment of various diseases ⁵³, Fennel seeds contain antioxidants as kaemoferol and quercetin that prevent degenerative reactions ⁵⁴.

Many researchers reported that micro vesicularsteatosis occurred due to changes in enzyme levels of hepatocytes. They emphasized that it was caused by oxidative stress resulting in mitochondrial degenerations ⁵⁵. The present results were confirmed with histological changes of feeding rats with high fat diet only, which showed vaculation of tunica media and narrowing in the lumen of aorta sections as well as congestion of cardiac blood vessel and hyalinosis of its wall. This result was confirmed by Szilvassy et al.⁵⁶ who indicated that although hyperlipidemia increases oxidative stress in the cardiovascular system, it renders the heart and the vasculature more susceptible to stress. Ouwens et al. ⁵⁷ identified that development of hyper-cholestremia which is one of the risk factors for cardio vascular diseases.

The high fat diet administration was associated with a highly significant increase in urea level as compared to the control group. Treatment with fennel, ator and fennel with ator following high fat diet administration exhibited a high drop in this elevation as compared to the obesity group and this indicated also that treatment with fennel with ator was near to the control value.On the other hand, fennel group and ator group supplement successes partially in improving the creatinine level in comparing with the obesity group. And although fennel and ator group indicated significant more decrease in creatinine level as compared to group(3) and group(4) but increase than the control. Uric acid level showed a significant increase in obesity group as compared as to the control value. The administration of fennel, ator and fennel with ator resulted in a partial improvement in the uric acid level as compared to the diabetic group .In the opposite direction the uric acid level of group (5) showed significant decrease comparing to group (3) and group(4). The data reported in the present work indicates that administration of high fat diet provoked a significant increase in serum ALT, AST and ALP. Treatment with (fennel) and (ator) induced a partial recovery but treatment by fennel with ator more improving the ALT, AST and ALP.The finding of this study indicates that the concentration of Malondialdehyde (MDA) and Myeloperoxidase (MPO) in liver homogenates of the fennel and ator group significant decrease than group (3) and group (4) and obesity group. There is a growing awareness that obesity is a prime risk factor for the development of dyslipidemic profile and that oxidative stress may play a role in various adverse effects of obesity.

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