Role of Flavonoids, Phenolics, and Saponins in Obesity Management: Molecular Pathways, Mechanisms, and Future Therapeutic Opportunities

Obesity is termed a long-time metabolic condition. This condition arises if in the long run energy absorbed as in food intake exceeds energy broken down essentially. It is characterized by fat deposition to such an extent that it becomes a health risk.[1]

The issues of being overweight and obese have been crowned as the most significant and tough health issues of modern times to tackle with and the count of people suffering from it has reached millions all over the world. In 2021, the World Health Organization (WHO) startled everyone by predicting that the total number of obese people was more than a billion, consisting of roughly 650 million adults, 340 million adolescents, and 39 million infants.[2]

Overweight or obesity is to a large extent a very significant factor affecting health. The excess fat in the human body may result in quite heavy medical problems, among which the most common are heart attacks and strokes, diabetes type 2, and ussical disorders like osteoarthritis as well as certain types of cancers such as endometrial, breast, and colon cancer. The previously mentioned diseases are not only the main causes of disability, but also cause death in a short period, thus resulting in loss of the life years.[3]

The notion, that obesity is primarily due to individual defects like pleasure-seeking behavior, no self-control or simply being over lazy, is still quite prevalent.[4]

At present, the FDA has granted approval for long-term use of five medications against obesity in the United States. The decrease in weight caused by these five anti-obesity drugs is in the following order from largest to smallest- Phentermine/topiramate > Liraglutide > Naltrexone/bupropion > Lorcaserin > Orlistat.[5]

Besides the high price, these medications come with adverse effects and their application in curing obesity is also limited.[6]

Owing to the massive costs and probable side effects of already available anti-obesity drugs, natural products are becoming more and more of a focus area among researchers who regard them as potential substitutes. The unrefined plant extracts and isolated compounds have demonstrated a reduction in the amount of fat in the body, as well as a manifestation of their potential through the prevention of obesity caused by diet, thus making them fit for the development of the new, safer, and more potent anti-obesity treatments.[7]

 The renowned phytochemical constituents which include terpenoids, flavonoids, saponin, phenol, and alkaloids consist of key biological benefits.  The phytomolecules would mediate their effects via the inhibition of pancreatic lipases, the differentiation of adipocytes, or by the augmentation of thermogenesis and the reduction of appetite. This review presents the anti-obesity properties of phytomolecules as a whole, but particularly focuses on Flavonoids, Phenolics, and Saponins, while at the same time looking into the mechanisms and pathways, they employ to combat obesity.[8]

Currently, the methods used to prevent and treat overweight and obesity problems consist of changing lifestyle (dietary) habits, using anti-obesity medications, and performing surgical operations.[9]

Nevertheless, though dietary modifications bring about only short-term results, a significant portion of the weight loss that occurs at the beginning is due to the elimination of glycogen and water, and the slowing down of the weight loss process in the long run.[10]

Among various treatment modalities, pharmacological and surgical interventions have definitely made a mark, yet these are restricted due to various reasons like not being effective enough, safety concerns, and controversy about the benefits over a long period of time, just like the case of orlistat, which is a weight loss drug that you can buy without a prescription, but its adverse effects include digestive system irritation, liver and kidney damage, [11] reduced absorption of fat-soluble vitamins (A, D, E, and K).[12]

On the other hand, most of the scientific research has shown that the incorporation of natural polyphenols such as flavonoids in the diet or through nutritional supplementation can be a safe and even more effective alternative for the treatment of obesity.[13]

OVERVIEW OF PHYTOCHEMICALS IN OBESITY MANAGEMENT

Phytochemicals are natural compounds that come from plants and are still among the most effective strategies for battling obesity due to their capacity to control crucial metabolic pathways like those of fats, energy, and appetites, along with the inflammatory signaling. They are also considered a factor in making obesity difficult to bear as the consumption of largest amounts of these compounds during the day even has dramatic effects on lowering overall body weight and fat, and on improving insulin sensitivity and metabolic profiles. Phytochemicals have, thus, become a major research focus not only for weight loss but also for health-improving properties as they have been found to act through several overlapping mechanisms like AMP-activated protein kinase (AMPK) activation, lipogenic inhibition, adipogenic transcription factors suppression, fatty acid oxidation elevation, and inflammation reduction. Phytochemicals have multiple mechanisms of action and are through to be less potent and to have a lower risk of adverse side effects compared to conventional anti-obesity medications, thus making them the preferred choice in the management of drug-resistant patients with obesity as a complementary or even primary therapeutic option [15].

FLAVONOIDS;

INTRODUCTION

Flavonoids are made up of a collection of phytochemicals [16] recognized as the low molecular weight polyphenolic secondary metabolic compounds, which are present throughout the green plant kingdom and are kept in vacuoles [17].

There is a wide range of foods containing such compounds, including fruits, vegetables, seeds, flowers, and leaves, and therefore, they are non-removable components of the human diet.[16]

They generally consist of flavonoids, such as flavonols, dihydroflavonols, isoflavones, and dihydroisoflavonols; chalcones and aurones; flavonoids, such as flavonols, isoflavones, dihydroflavonols, and chalcones; and the colored anthocyanidins and biflavonoids. [18]

An exceedingly high number of the flavonoids are acknowledged to be therapeutically effective. [19]

Natural synthesis occurs through the phenylpropanoid route; the biological activity depends on an absorption mechanism and bioavailability. [20]

CHEMICAL STRUCTURE   

(Fig. 1), 2-phenyl-2,3-dihydro-1-benzopyran.

Flavonoids vary enormously in their chemical structures, but the basic framework is made up of 15 carbon atoms (C6-C3-C6) that form two aromatic rings (A and B) linked by a 3-carbon chain which leads to an oxygenated heterocycle (C).[21] (Figure 1).

Flavonoids are derivatives of 1, 3-diphenylpropan-1-one, and the route of their synthesis is one p-coumaroyl-CoA molecule along with three malonyl-CoA molecules condensing to form the intermediate chalcone. [22]

Flavonoids, which are water-soluble pigments, are present all over the plant kingdom, [23] and more precisely, they are the cytosol and vacuole of plant cells where they are stored. [24]

Classification and sources of Flavonoids  

Flavonoids consist of many different subclasses, which are primarily identified by changes that occur in the C-ring. The most important subclasses are ;

According to Shen et al. (2022), the basic skeletal structure of flavonoids, the classes of flavonoids, and their sources of food are the following: [25]

(a) The basic structure of flavonoids.

(b) The principal types of flavonoids.

(c) The natural sources of the different types of flavonoids in plants.

FLAVONOIDS ROLE IN ANTI OBESITY.

The reason is that these compounds reduce the pathogenic processes like stress caused by free radicals and resulting in fat deposition inside the cells, increase of white fat tissue, changing of gene expression, gut bacteria, and inflammation and among others, and thus they can be considered as the treatment of obesity and its health problems with low cost and fewer side effects. [26]

PHENOLICS

INTRODUCTION

Phenolic compounds are the most significant non-essential dietary components derived from plants' secondary metabolite production which appeared at a high group level in the food chain and throughout the various stages of production. Phenolic compounds are most often ether in nature though occasionally they are referred to as alkane. They have been identified to date over 8000 phenolics with a very diverse range of chemical structures [27].

At first, food coloring agents were natural phenolic compounds but, since the 1990s, their usage as part of a diet has been the core of scientific inquiry due to the fact of discovering that such diets reduce the risk of chronic diseases of the heart and cancer, among others. Phenolic compounds are generally categorized into two principal classes: the first one is the flavonoids, which are the polyphenol group having the C6–C3–C6 structure, and the second one is the non-flavonoids with the most important being the phenolic acids in the food supply. Among the various groups of phenolic compounds, which are represented by epigallocatechin gallate (EGCG), resveratrol, catechin, quercetin, procyanidins, and anthocyanins, and others, the most significant to the health area are the ones with anti-obesity activities which not only include adipogenesis inhibition but also the activation of AMPK and SIRT1 pathways. The research on this specific group of phenolic compounds is very extensive.[28]Chemical structure

Fig 2; Phenol

The main characteristic of phenolic compounds is that they have at least one aromatic benzene ring, which is known as a phenyl ring, and one or more hydroxyl (–OH) groups are attached to it. The primary phenol unit is their mutual structural foundation, and it is the basis of all the phenolic subclasses, namely, phenolic acids, stilbenes, lignans, tannins, and polyphenol-related compounds. Their molecular structures can be as simple as that of gallic acid and caffeic acid or as complex as proanthocyanidins and ellagitannins that are formed through polymerization. This specific arrangement of aromatic and hydroxyl groups in phenols is responsible for the wide-ranging biological activities of phenols, including strong antioxidant potential, metal ion chelation, and free-radical scavenging (Figure 2).[29]

“The classification and sources of phenolics” [30]

Phenolic compounds form a very heterogeneous group of metabolites that are produced by plants and are classified according to the number of aromatic rings, the presence of hydroxyl groups, and the characteristics of the side chain. The main phenolic compounds in human diet are phenolic acids, stilbenes, lignans, tannins, and other complex polyphenols, which are all present in large amounts in various plant-based foods.

1. Phenolic Acids

These are the foremost phenolic compounds in human food.

1. Hydroxybenzoic acids

All of the above-mentioned acids, namely gallic acid, vanillic acid, syringic acid, and protocatechuic acid, are some of the phenolic acids that are obtainable from a variety of natural products such as berries, pomegranate, nuts, tea and even certain spices.

2.  The hydroxycinnamic acids

The two categories made up of these elements can be distinguished with the first one mainly consisting of the acids like caffeic, chlorogenic, ferulic, and p-coumaric, while the second group is largely formed of coffee, apples, and whole grains, although the latter sources do also include to some extent carrots, leafy vegetables, and tomatoes.

2. Stilbenes are represented by the likes of resveratrol and piceatannol which occur naturally in grapes, red wine, peanuts, and berries.

3. Lignans are another plant group containing secoisolariciresinol, matairesinol, and sesamin which are mainly found in flaxseed, sesame seed, whole grains, and legumes.

4. Tannins, also known as Polymer Phenolics, can be of two main types, i.e. Hydrolysable tannins which include gallotannins and ellagitannins that can be sourced from pomegranate, walnuts, and berries, and Condensed tannins (Proanthocyanidins) like procyanidins and catechin polymers that are found in cocoa, grape seeds, cranberries, and blackcurrants.

1. The last category of other polyphenols is headed by curcumin (phenolic terpene), tyrosol, and hydroxytyrosol, with turmeric, olives, and spices or herbs being the primary sources, respectively.

Phenolics in Anti-Obesity

The ability to prevent obesity is one of the prime effects of phenolic compounds and this is achieved by their modulation of several key metabolic routes. These agents are seen to reduce the stress level of the organism, inhibit the storage of lipids in adipose tissues, and arrest the growth of fat cells via modulation of the genes including PPAR-γ, C/EBP-α, and AMPK. Following this, the phenolic compounds further uplift the functionality of mitochondria, lower the inflammation, and also the gut's microbial population is altered in a way that is beneficial to the production of SCFAs which in turn supports metabolism.

The overall impact of these phenolic compounds, among which are chlorogenic acid, caffeic acid, ferulic acid, resveratrol, catechins, quercetin, and proanthocyanidins, has been acknowledged as an anti-obesity measure that is not only effective but also natural and safe.[31]

SAPONINS;

INTRODUCTION

Saponins are glycosides existing in nature composed of a non-polar aglycone (sapogenin) linked to one or several sugar chains. They are categorized based on the type of sapogenin as either triterpenoid or steroidal and occur in great amounts in medicinal plants, pulses, cereals, and spices. Their use in the treatment of obesity has been a subject of research over the last few years, which is one of the reasons they have become popular for their metabolic benefits. Inhibition of pancreatic lipase, reduction of dietary fat absorption, suppression of adipocyte differentiation, and improvement of insulin sensitivity are some of the actions that saponins have. Additionally, modulation of inflammatory outbreaks can also occur.   Some saponins, in addition to the ones mentioned above, enhance glucose uptake and positively influence gut microbiota, which in combination leads to weight loss and improved metabolic health. The actions of combatting multiple targets make saponins the light of nature that is not only for the prevention but also for the treatment of obesity.[32]

Chemical structure

Fig 3; SAPONINS

Saponins, which are glycosides, exhibit both hydrophobic and hydrophilic characteristics and they are the ones that are distinguished by the existence of a hydrophobic aglycone (sapogenin) that is connected to either a single or multiple hydrophilic sugar chains. The aglycone could be a triterpenoid (C30) or a steroidal nucleus while the sugar part usually consists of glucose, galactose, rhamnose, xylose, arabinose or glucuronic acid. The surface-active characteristics of saponins as well as their capability of producing stable foams in water can be attributed to the unique glycone–aglycone structure. Regarding the structure, in dicot plants the predominant group are triterpenoid saponins, while in monocot species steroidal saponins are the main ones. The fact that they have amphipathic properties is what makes them involved in various biological activities such as enzyme inhibition, interaction with membranes, and metabolic regulation.[33]

Classification and sources of Saponins [34]

1. Triterpenoid Saponins

Triterpenoid saponins are the most typical ones among the higher plants and are made from a C30 triterpene skeleton. Examples

• Ginsenosides (Panax ginseng)
• Soyasaponins (soybean)
• Quillajasaponins (Quillaja saponaria)
• Oleanolic acid saponins
• Hederacoside C, α-hederin (ivy)

Sources; Legumes (soybean, chickpeas, lentils), quinoa, oats, spinach, ginseng, licorice, ivy leaves.

2. Steroidal Saponins

These compounds occur primarily in certain plants with only one cotyledon, and they have been formed from a C27 corticosteroid nucleus

Examples

• diosgenin
• dioscin
• yamogenin
• tigogenin
• gracillin

Herbicide-resistant crops are godsend as they contain fungicides that are safe even for human beings but harmful to insects and pests.

3. Marine Saponins

These saponins are mainly found in marine creatures, particularly in echinoderms.

Examples

• Holothurins
• Asterosaponins

Sources; Sea cucumbers, starfish.

4. Diet Saponins

The saponins are those found in food from the very beginning.

Illustrations

• Soyasaponin A and B
• Quinoa saponins
• Tomato saponins
• Lentil and chickpea saponins

Sources

Quinoa, legumes, spinach, oats, tomatoes, garlic

Saponins in Anti-Obesity [35]

Saponins are considered one of the main substances affecting obesity negatively. They act like blockers of pancreatic lipase and thus fat is absorbed less than it would normally be. Besides this, they also keep fat cells from maturing, they do that by modifying genes such as PPAR-γ and C/EBP-α. Saponins excite AMPK, and that accelerates the process of burning fat and upgrading the condition of the mitochondria. Furthermore, they are anti-inflammatory agents through blocking NF-κB and they are the modulators of the gut microbiota, thus enabling the body to have better glucose and lipid metabolism. These overlapping activities have resulted in the reports of the weight decrease, better lipid profiles, and increased metabolic health caused by the saponins of ginseng, soy, fenugreek, quinoa, and sea cucumbers.

PATHOPHYSIOLOGY OF OBESITY

Obesity is the result of a chronic energy imbalance situation, but the mechanism of its pathophysiology is through complex interactions between adipose tissue dysfunction, inflammation, hormonal imbalance, gut microbiota alterations, and metabolic dysregulation. Weight gain leads to an increase of fat cell size (hypertrophy) as well as number (hyperplasia), which results in the decline of their functional capability and the increase in their secretion of free fatty acids (FFAs) and cytokines like TNF-α and IL-6 that promote inflammation. One of the factors that trigger diabetes development is this low-grade inflammation since it reduces the effectiveness of insulin, disrupts the utilization of glucose, and causes abnormal deposits of fat.

Adipose tissue that is not functional also impacts the production of adipokines: the condition of leptin resistance occurs even though the leptin levels are high, while the amount of adiponectin decreases, thus the process of fatty-acid oxidation is hindered. The belly fat that is too much also takes part in the formation of the liver and muscle problems associated with the deposit of abnormal fat leading to the occurrence of non-alcoholic fatty liver disease and metabolic dysregulation. Moreover, the bacterial population in the gut that is less healthy can not only lead to more energy being harvested from food but also to the inflammatory process by turning into metabolic endotoxemia through lipopolysaccharide (LPS) that causes the translocation of bacteria in the system.

These factors combined create a vicious cycle of metabolic impairment, inflammation, and fat storage which is typical for obesity and its associated diseases.[36]

MOA OF FLAVANOIDS IN OBESITY MANAGEMENT

Flavonoids have a powerful impact on the body fat issue by intervention in processes like differentiation, metabolism of fat, insulin signaling, and inflammation. They obstruct the formation of fat cells by decreasing the activity of PPARγ and C/EBPα/β and preventing fat cell development by preventing SREBP-1c and downstream lipogenic enzymes (FAS, ACC, SCD-1). Flavonoids cause AMPK to be activated, which increases the rate of fatty acid burning and mitochondrial β-oxidation and thus metabolism is changed from storage of fat-to-fat usage. Besides this, they help to be more responsive to insulin by activating the IRS-1/PI3K/Akt pathway and directing more GLUT4 to the cell surface. Their anti-inflammatory and antioxidant activities that are achieved by the suppression of NF-κB and the decline of oxidative stress are other factors that support the metabolic balance and lower body fat. [37-44]

MOA OF PHENOLICS IN OBESITY MANAGEMENT

Phenolic compounds are able to reduce body fat and prevent its accumulation by changing the ways the body uses fats, decreasing free radicals, reducing inflammation and regulating glucose levels. They block the formation of new fat cells (adipogenesis) and the conversion of fat to cells (lipogenesis) by preventing the action of PPARγ and SREBP-1c, respectively, and consequently there will be less manufacturing of fatty acids and triglycerides. The ingestion of these substances activates the AMPK enzyme, which leads to the burning of fats (oxidation) in the mitochondria and hence the production of energy (ATP) is increased. Also, the phenolics increase the effectiveness of the insulin hormone by facilitating the signaling (IRS-1/Akt) and the movement (GLUT4 translocation) of the glucose transporter (GLUT4) located inside the cell. Their powerful capabilities as antioxidants and anti-inflammatories, which are attributed to their ability to activate Nrf2 and inhibit NF-κB, transfer adipose tissue from the harms of obesity-induced damage. Moreover, phenolic substances have a positive effect on the gut microbiota by raising the production of short-chain fatty acids which in turn leads to better metabolic balance and helps the body to discard the unusable fats and sugars more efficiently. [45-53]

MOA OF SAPONINS IN OBESITY MANAGEMENT

The anti-obesity impact of saponins is mainly through their action of hindering fat absorption from diet and storing less lipids in adipocytes. They act on pancreatic lipase and thus absorb less fat in the intestine and excrete more fat in stools. Additionally, saponins deplete lipids in a manner similar to that of downregulation of PPARγ and C/EBPα responsible for adipogenesis and they also conduct reduction of triglyceride accumulation in adipocytes. With the upregulation of AMPK signaling, there is a subsequent increase in the process of burning fatty acids and hence reduction in the generation of energy from fats. Moreover, saponins have the capacity to combat inflammation and also have an influence on the composition of gut microbes thus facilitating better lipid as well as glucose metabolism. All these processes together lead to a decrease in fat mass and an enhancement of metabolic health. [54-57]

PATHWAYS IN ANTI OBESITY

1. AMPK PATHWAY

AMPK and the Link with Anti-Obesity

1. AMPK Inhibits Lipogenesis [58]

When AMPK is activated, it first of all phosphorylates and then inhibits ACC1/ACC2, thereby leading to the reduction of malonyl-CoA which is a key substrate for fatty-acid synthesis. At the same time, it also inhibits the expression of lipogenic enzymes such as FAS and SCD-1 further down the line, which contributes to lipid synthesis being reduced and fats being less stored.

Result: ↓ Fat synthesis, ↓ lipid accumulation.

2. AMPK also Stimulates Fatty Acid Oxidation (FAO) [59]

The increasing of malonyl-CoA by AMPK removes CPT-1 inhibition and thus makes it possible for fatty acids to come into the mitochondria. In the mitochondria, AMPK stimulates β-oxidation which is the process of breaking down fatty acids into acetyl-CoA and consequently raises energy expenditure.

Result: ↑ Fat burning during exercise, either due to up-regulation of β-oxidation in muscle and/or increased oxidative phosphorylation.

3. AMPK augments lipolysis [60]

The enzymes involved in lipolysis namely ATGL, HSL, and MGL which are also the main targets of AMPK activation, convert the triglycerides into free fatty acids and glycerol. The released fatty acids are oxidized in the mitochondria.

Effect: ↑ Fat depots reduction. 

4. AMPK Insulin Sensitivity [61]

AMPK increases the transport of GLUT4 to the plasma membrane, raises glucose uptake, and lessens the accumulation of fats in the tissues, thereby enhancing the insulin sensitivity in the entire body.

Outcome: low blood glucose and reduced lipotoxicity.

5. AMPK Supports Thermogenesis [62]

AMPK through PGC-1α activation promotes the formation of new mitochondria by increasing their number and also stimulates the expression of UCP1 in the brown and beige fat tissues, thus enhancing the production of heat and consumption of energy in the body.

Result, there are more heat and more calories consumed.

2. PPARγ Pathway (Peroxisome Proliferator–Activated Receptor Gamma)

1, PPARγ Regulates Adipogenesis (Fat Cell Production) [63]

PPARγ is the leading transcription factor that transforms preadipocytes into fully developed adipocytes. The downregulation of PPARγ results in a decline in adipocyte differentiation because of the lowered expression of the adipogenic markers C/EBPα, C/EBPβ, and FABP4.

Result; ↓Decrease in development of new fat cells↓Decrease in fat tissue development.

2. “PPARγ regulates the expression of genes involved in lipid uptake and         triglyceride storage in adipocytes.” [64]

PPARγ up-regulates gene expressions associated with lipid uptake and storage like LPL, CD36, and aP2/FABP4. If the PPARγ pathway is interrupted, adipose tissue's lipid imports as well as triglyceride accumulation is down and the cells get smaller.

Result: Lipid accumulation is lowered, and triglyceride storage is also lowered.

3. PPARγ has an impact on metabolic flexibility [65]

PPARγ overstimulation brings about the storage of fats (anabolic).

Metabolic shift from fat storage to burning, enhancement of mitochondrial functionality, and less fat accumulation in adipocytes are the benefits of downscaling.

The outcome is greater burning of fat and improved metabolic efficiency.

4. PPARγ Modulates Inflammation [66]

PPARγ in a way controls the inflammatory around signaling adipose tissue.

The reduction of the receptor gives rise to a decrease in the inflammatory cytokines TNF-α, IL-6, and MCP-1, enhancing insulin signaling, and lowering metabolic disorders.

The reduced inflammatory reactions lead to the increase of insulin sensitivity.

3. PI3K/Akt Pathway

1. PI3K/Akt gets lead in the uptake of glucose [67]

Insulin induces the activity of PI3K, the result of which is the synthesis of PIP3 and the activation of Akt.

The final result of this process is that Akt causes the movement of GLUT4 from the cytosol to the cell membrane in muscle and fat tissues.

Outcomes:

• Increase in glucose uptake
• Decrease in blood glucose
• Decrease in the conversion of glucose to fat

2. PI3K/Akt Decreases the Rate of Lipogenesis and Lipid Storage [68]

Akt lessens the build-up of internal lipids in the following ways:

• enhancing the sensitivity to insulin
• reducing the level of glucose in blood
• lowering the nutrient supply for the formation of triglycerides

Result:

• Less fat accumulation
• Less enlargement of fat cells

3. PI3K/Akt Modulates Adipogenesis [69]

Activation of PI3K/Akt:

• Supports normal activities of the fat cells
• Stops the changes in the functioning of adipocytes that occur during obesity

Result:

• Even adipogenesis
• Less pathological fat deposits

4. PI3K/Akt Enhances Insulin Sensitivity [70]

Akt Activation:

• Stops Inflammation Signaling
• Stimulates Actions of Insulin Receptor (IRS-1)
• Blocks Insulin Resistance

Result:

• Improved glucose metabolism
• This goes hand in hand with lower rates of obesity-related diabetes.

4. NF-κB Pathway in Anti-Obesity

Pathogenic processes due to activation of the renin–angiotensin–aldosterone system (RAAS) are involved with the formation of atherosclerosis. When the body is in such states, NF-κB gets turned on and translocates to the nucleus where it stimulates the transcription of inflammatory genes.

The activated NF-κB:

- by inducing cytokines (TNF-α, IL-6, MCP-1) that are pro-inflammatory, brings about inflammation in adipose tissue

- through the disturbance of the insulin receptor signaling, reduced glucose uptake, and high blood glucose, causes resistance to insulin

- through the reduction of fatty acid oxidation and the increase in the accumulation of lipids, it also does this in the liver, thus contributing to the overall metabolic dysregulation

Flavonoids and phenolics among others found in nature are known to block NF-κB activation leading to a reduction of inflammation, enhancement of insulin sensitivity, decrease of liver fat accumulation, and protection against the development of metabolic disorders related to obesity.

Conclusion: The blockade of NF-κB leads to the improvement of metabolic health and the prevention of complications related to obesity.[71]

5. SREBP-1 Pathway in Anti-Obesity

1. SREBP-1c Activation [72]

When there is a lot of glucose and insulin in the body, the PI3K/Akt pathway is activated, which in turn transforms SCAP into its active form. The active SCAP then carries SREBP-1c from the endoplasmic reticulum to the Golgi apparatus where it is cut. The resulting SREBP-1c goes to the nucleus where it turns on the genes responsible for the formation of fats. Besides, natural substances are able to prevent the activation of SCAP and SREBP-1c.

Outcome:

• SREBP-1c activation was decreased
• Lipogenic gene expression was reduced

2. SREBP-1c activity increases lipogenesis through elevation of fatty acids and triglycerides synthesis.[73]

SREBP-1c, when activated, recruits a series of lipogenic enzymes including ACC, FAS, and SCD-1 to its side by virtue of their increased expression. The result is the fatty acid and triglyceride production being doubled and eventually leading to the fat being stored and the adipocytes being enlarged.

Outcome:

• Fat and triglyceride production has been increased
• Enlargement of adipocytes

3. SREBP-1c activates uptake proteins for lipids such as LPL and CD36 which enable fatty acids to flow into adipose tissue in larger amounts. Consequently, this process leads to the increase in the size of fat cells and it also plays a role in the rise of blood glucose levels due to the overload on metabolism. [73]

Outcome:

• Lipid uptake increased
• Adipocytes enlarged
• Blood glucose elevated

4. SREBP-1c down-regulates the activity of fatty acid synthesis genes, consequently leading to a diminished mitochondrial fatty acid oxidation. This change results in less fat burning, glucose intolerance, and general metabolic dysfunction. [74]

Result:

• SREBP-1c inhibition callbacks the fatty acid oxidation
• Better glucose utilization

COMPARISON TABLE OF FLAVONOIDS, PHENOLICS, AND SAPONINS

TABLE 1

Interpretation: The mechanisms of anti-obesity actions of flavonoids, phenolics, and saponins are complimentary whereby the two latter ones mainly influencing the intracellular metabolic and inflammatory pathways and saponins being the ones that mainly reduce lipid absorption. The variations in clinical trials point out the flavonoids as the most clinically validated group.

TABLE 2. Expanded preclinical evidence of phytochemicals in obesity models

Interpretation

The results of preclinical researches indicate that the anti-obesity effects of flavonoids, phenolics and saponins are consistently anti-obesity through the mechanisms which include reduction of adipogenesis, increase of fatty-acid oxidation, bettering of insulin sensitivity, and controlling of inflammatory and mitochondrial pathways.

TABLE 3. Expanded clinical evidence of phytochemicals in obesity models