Effects of Coconut Oil long-term supplementation in Wistar rats during Metabolic Syndrome - regulation of metabolic conditions involving Glucose Homeostasis, Inflammatory Signals, and Oxidative Stress.

The global prevalence of obesity and overweight has increased significantly since 1980, mainly due to positive energy balance and sedentary life habits. These conditions negatively influence all the body's physiological functions, affecting productivity, quality of life, and healthcare costs for these individuals. The main drivers of this epidemic are the overconsumption of high-calorie, nutrient-poor, processed food and beverages and reduced physical activity [1], [2], [3]. During this condition, the positive energy balance will produce excessive triglycerides stored in adipose tissue, resulting in increased body fat and weight.

Metabolic Syndrome (MetS) is a multi-factorial disease, including a cluster of pathologies most commonly seen together than by chance [4]. Reviews have found that the conditions associated with MetS are visceral obesity, insulin resistance, hypertension, high triglyceride levels, and low High-density Lipoprotein (HDL) cholesterol, leading to type 2 diabetes [4], [5], [6], [7], also, Grattagliano et al., have reviewed the involvement of oxidative stress in this pathology [8]. Symptoms of MetS can be explained as manifestations of age; however, early life habits and excessive calorie intake can lead to a future MetS diagnosis. Nutrition is a modifiable lifestyle element and can directly influence health. Therefore weight control and preventive nutrition have become a focus for consumers and food providers [9]. According to Basciano, diets high in saturated fats positively affect factors related to the MetS; however, it has not declined the obesity epidemic. Therefore, it is suggested that fat is not the only culprit behind metabolic disorders and that increases in carbohydrate consumption, mainly refined sugar high in fructose, have an emerging role in the obesity epidemic [9], [10], [11]. In addition, poor eating habits like the usual westernized diets, rich in high-fat and high-sugar products and drinks, and unhealthy habits such as smoking and sedentary behavior have contributed to the rise in metabolic disorders and increased fat and sugar consumption worldwide.

Oxidative stress can be briefly described as an imbalance between the production of reactive species and the ability to detoxify the molecules produced or repair the resulting damage. Through this, oxidative stress will result in intermediates that will either be repaired or accumulate in the cells [12]. Increased oxidative stress is associated with elevated adiposity and insulin resistance in men [13] and also found in those with MetS [14], suggesting that oxidative stress could be an early event in MetS related manifestations, like atherosclerosis, hypertension and type-2-diabetes [15,16]. Peroxynitrite is one of these species and will induce protein nitration, especially those of tyrosine residues leading to elevated levels of nitrotyrosine (NOS). Tyrosine nitration is observed in vivo in healthy tissues and cells [17], however increased levels are found in several conditions like obesity [18], MetS [16] and dementia [19]. During the abstraction of an H+ from a carbon present in a given lipid molecule, a Carbon-Radical is formed because of the remaining unpaired electron of the carbon atom. Usually, this radical is stabilized by a molecular rearrangement to form a conjugated diene. However, during aerobic conditions, this Carbon-Radical will most likely combine with O2 to form a peroxyl radical which is capable of abstracting H+ from another lipid molecule, causing the propagation of lipid peroxidation; because of this, a single initiation event can lead to the formation of multiple lipid peroxides as the result of a chain reaction [20]. Following conjugated dienes rearrangement there is the formation of alkanes, aldehydes and isoprostanes. The largest family of aldehydes generated from lipid peroxidation is constituted by 4-hydroxy-2-alkenals, from which the most abundant member is 4-hydroxy-2-nonenal (4-HNE) [12]. Oxidative stress has been considered an important secondary consequence of inflammation, mainly because the inflammation causes cytokine release and altered mitochondrial activity, which shall lead to increased generation of reactive species at different intracellular levels [21]. In light of these works, it becomes clearer that sustained inflammation in adipose tissue and other organs will lead to inflammatory signals, both locally and systemically. These inflammatory signals will cause an oxidative imbalance leading to the accumulation of damaged molecular targets, like NOS, conjugated dienes and 4-HNE.

Fructose is a sugar highly used as an industrial sweetener in many soft drinks and juice beverages while also used in many pre-packaged foods, mainly in the form of High Fructose Corn Syrups (HFCS). Frequently, only one package of a given soft drink is enough to reach the daily-recommended fructose dose. In addition, due to these uses, fructose ingestion and global consumption have increased dramatically in the last 20 years, and for these reasons, individual fructose overconsumption has become a significant concern. Many authors have reported the role of increased Fructose consumption in animal models, indicating that it leads to increased adiposity [22], increased serum triglycerides (TGs) [23,24], insulin resistance [22,24,25], hypertension [25,26], increased inflammatory signaling [24,27] and elevated oxidative stress [26] sometimes leading to lipoperoxidation of macromolecules [23,24,28].

In recent years, Coconut Oil (C.O.) has been the target of much media speculation and commercial interest due to its satiating properties and capacity to aid weight loss [29]. C.O. presents a high content of Medium-Chain Triglycerides; however, it also possesses a considerable content of lauric acid with 12 carbons, considered a medium-chain saturated fatty acid, and thus, its use should be cautious. The recent studies involving C.O. supplementation [30], [31], [32] have reported inconsistent results; most of the data includes short-term supplementation via diet, using C.O. instead of other oils like soybean oil, or short-term supplementation via gavage. Among all fat sources, C.O. has the highest known amount of saturated fats (about 90%); authors have reported that its continued consumption can increase low-density lipoprotein (LDL). Although it has gained popularity in the last few years, with an exponential increase in sales and consumption, to our knowledge, no agency or health association encourages its use. The lack of data and this increase in its popularity makes studies showing the long-term effect of C.O. administration and its effect on disease pathophysiology a must, particularly in diseases where fat and carbohydrate intake play a pivotal role, like MetS and type-2-diabetes.

Our work aimed to bring light on C.O. supplementation and its potential health risks or benefits. We chose a long-term model of MetS using Fructose to mimic some of the effects observed in the syndrome, like increased adiposity, dyslipidemia, and hepatic injury. Moreover, we targeted three main parameters involving MetS; increased presence and breakdown of White Adipose Tissue, triglycerides and cholesterol levels, and glucose homeostasis during fasting. Additionally, we further explored the role of oxidative stress inflammatory signaling during MetS and C.O. supplementation.

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