Current Evidence of Natural Products against Overweight and Obesity: Molecular Targets and Mechanisms of Action

: Overweight and obesity are global health and economic concerns. This disease can affect every system of the human body and can lead to complications such as metabolic syndrome, diabetes, cancer, dyslipidemia, cardiovascular diseases, and hypertension, among others. Treatment may sometimes include diet, exercise, drugs, and bariatric surgery. Nonetheless, not all people have access to these treatments, and public health strategies consider prevention the most important factor. In this regard, recent investigations are aiming to find alternatives and adjuvants for the treatment of obesity, its prevention, and the reversion of some of its complications, using natural sources of anti-obesogenic compounds like polyphenols, terpenes, alkaloids, and saponins, among others. In this review, we gather the most current information using PubMed, Google Scholar, Scopus, Cochrane, and the Web of Science. We present and discuss the current information about natural products that have shown anti-obesogenic effects at a molecular level. We also consider the impact of dietary habits and lifestyle on preventing overweight and obesity due to the evidence of the benefits of certain foods and compounds consumed regularly. We discuss mechanisms, pathways, and receptors involved in the modulation of obesity, especially those related to inflammation and oxidative stress linked to this disease, due to the relevance of these two aspects in developing complications.


Introduction
Over the past few decades, the number of adults aged 18 and older who are overweight or obese has been increasing worldwide.Overweight and obesity are defined as having a body mass index (BMI) greater than 25 kg/m 2 and 30 kg/m 2 , respectively [1].Overweight and obesity are health issues that greatly affect public health and are linked to socioeconomic factors.Some groups are more affected than others.For example, in the United States, non-Hispanic black adults have the highest prevalence of obesity, followed by Hispanic adults, non-Hispanic white adults, and non-Hispanic Asian adults.Furthermore, the total prevalence of overweight and obesity among adults aged 20-39 is 39.8%.Additionally, the burden of overweight and obesity is also influenced by the degree of education; for instance, it has been reported that men and women with college degrees have a lower prevalence of obesity compared with those with less education [2,3].Other factors that are important in the incidence of weight disorders are genetic, behavioral, environmental, and lifestyle factors.Particularly, sedentarism and low metabolic rate, diet, genes, and metabolism are the main traits of this disease in current times [4].
Being overweight and obese, as a public health problem, represents a high burden on public expenditure in health care systems.In this sense, people living with obesity have 30% higher medical costs than normal-weight individuals [5].Currently, weight disorders have a strong association with non-communicable diseases such as diabetes mellitus, hypertension, metabolic syndrome, stroke, sleep apnea, gastrointestinal cancers, and inflammatory diseases [6].
An adequate diet, behavioral changes, and exercise are considered the cornerstones of obesity treatment.Nonetheless, for some patients, other measures are necessary, so the treatment includes anti-obesity pharmacotherapy [7].Modern anti-obesity drugs act mainly through three different mechanisms: reducing nutrient absorption, increasing energy expenditure, and suppressing appetite.Orlistat is a commonly used drug that inhibits the intestinal absorption of dietary fats.Energy expenditure is increased by using drugs that are agonists of GLP-1 Ras (glucagon-like peptide-1 receptor agonists).These are used for patients with obesity and diabetes due to their effect on the modulation of glycemic control.Phentermine is an example of an appetite suppressant that works by blocking norepinephrine uptake or stimulating its release [8,9].According to the Mayo Clinic, there are six weight-loss-approved drugs, including bupropion-naltrexone, liraglutide, orlistat, phentermine-topiramate, semaglutide, and setmelanotide.It is important to mention that their side effects are well documented, such as diarrhea and constipation, nausea, vomiting, tiredness, insomnia, headaches, depression, and others.Some effects may disappear over time, but this depends on each patient.Also, it is important to mention that, in rare cases, they may cause liver injury [10].Natural sources of anti-obesity compounds have shown little to no side effects, are usually easier to access than prescribed drugs, and are aimed at being used as prevention or adjuvants for obesity [11].
Obesity is a multifactorial and multisystem civilization disease; its cause is not only limited to inadequate nutrient consumption but to many different factors that contribute to its development and complications.Genetic and epigenetic factors are involved, and each individual presents different characteristics, lifestyle, tolerance to pharmacological treatment, socioeconomical circumstances, etc. [12][13][14].Therefore, research focusing on natural products as adjuvants in overweight and obesity has been highly reported in the past ten years, aiming to dilucidate mechanisms, dosages, sources, and other aspects of the safe and effective use of natural anti-obesogenic agents [11,[15][16][17].
Global efforts to reduce the burden of weight disorders are focused on dietary and lifestyle modifications, such as restricted calorie intake and increased physical activity, which are the most recommended.Within the food factors, there are some food ingredients, such as phytochemicals, that have been associated with weight loss agents or adjuvants.Polyphenols, alkaloids, and saponins are among the most widely studied phytochemicals in interdisciplinary studies evaluating their anti-obesity mechanisms of action.Here, we summarize current studies regarding the potential anti-obesity potential of these groups of phytochemicals.
1.1.Main Categories of Secondary Metabolites 1.1.1.Polyphenols Phenolic compounds are a heterogeneous group of secondary metabolites derived from the phenylpropanoid and phenylpropanoid acetate pathways.They have a structure with an aromatic ring that is composed of one or more -OH radicals (Figure 1).Furthermore, they are ubiquitously present in the plant kingdom, and their classification is based on the number of carbons in the molecules.They can be classified into several categories, including flavonoids, phenolic acids, lignans, and stilbenes.These compounds can be commonly found in the human diet, including foods such as fruits and vegetables, cereals, herbs, and spices, as well as beverages such as wine, tea, and coffee.The concentration and type of polyphenols in different food products depend significantly on the origin, cultivation, environmental conditions, maturity, pre-and post-harvest, storage, and transportation.Furthermore, these compounds have been widely studied for their beneficial health effects, highlighting their antidiabetic, anticancer, and anti-inflammatory effects, among others [18][19][20].
Furthermore, they are ubiquitously present in the plant kingdom, and their classification is based on the number of carbons in the molecules.They can be classified into several categories, including flavonoids, phenolic acids, lignans, and stilbenes.These compounds can be commonly found in the human diet, including foods such as fruits and vegetables, cereals, herbs, and spices, as well as beverages such as wine, tea, and coffee.The concentration and type of polyphenols in different food products depend significantly on the origin, cultivation, environmental conditions, maturity, pre-and post-harvest, storage, and transportation.Furthermore, these compounds have been widely studied for their beneficial health effects, highlighting their antidiabetic, anticancer, and anti-inflammatory effects, among others [18][19][20].

Alkaloids
Alkaloids are natural organic compounds found in a wide variety of plants that contain nitrogen.Their common structure is a heterocyclic ring with one or more nitrogen atoms, and they are classified into several categories, including indole, isoquinoline, pyridine, piperidine, tropane, and quinolizidine.Alkaloids are found in a wide variety of foods, such as tea, coffee, fruits and vegetables, spices, legumes, and nuts, and their distribution in the human diet varies according to geographic region and dietary habits.Furthermore, their bioavailability can be affected by several factors, such as the food matrix, the way of processing, and the intestinal microbiota, among others [21][22][23].Some of the most studied bioactive alkaloids, which are discussed in this review, are shown in Figure 2.

Saponins
Saponins are a group of chemical compounds found in a wide variety of plants that have a common steroid or triterpenoid ring structure with one or more hydroxyl groups; some of the most common saponins are ginsenoside, lupeol, and furostan (Figure 3).They can be classified into several categories, including steroids and triterpenes.These compounds are found in a wide variety of foods, including legumes, cereals, fruits, vegetables, tea, coffee, cocoa, and spices.These secondary metabolites have been studied for their anti-inflammatory, antioxidant, antitumor, antidiabetic, and antiviral properties, among

Alkaloids
Alkaloids are natural organic compounds found in a wide variety of plants that contain nitrogen.Their common structure is a heterocyclic ring with one or more nitrogen atoms, and they are classified into several categories, including indole, isoquinoline, pyridine, piperidine, tropane, and quinolizidine.Alkaloids are found in a wide variety of foods, such as tea, coffee, fruits and vegetables, spices, legumes, and nuts, and their distribution in the human diet varies according to geographic region and dietary habits.Furthermore, their bioavailability can be affected by several factors, such as the food matrix, the way of processing, and the intestinal microbiota, among others [21][22][23].Some of the most studied bioactive alkaloids, which are discussed in this review, are shown in Figure 2.
Furthermore, they are ubiquitously present in the plant kingdom, and their classification is based on the number of carbons in the molecules.They can be classified into several categories, including flavonoids, phenolic acids, lignans, and stilbenes.These compounds can be commonly found in the human diet, including foods such as fruits and vegetables, cereals, herbs, and spices, as well as beverages such as wine, tea, and coffee.The concentration and type of polyphenols in different food products depend significantly on the origin, cultivation, environmental conditions, maturity, pre-and post-harvest, storage, and transportation.Furthermore, these compounds have been widely studied for their beneficial health effects, highlighting their antidiabetic, anticancer, and anti-inflammatory effects, among others [18][19][20].

Alkaloids
Alkaloids are natural organic compounds found in a wide variety of plants that contain nitrogen.Their common structure is a heterocyclic ring with one or more nitrogen atoms, and they are classified into several categories, including indole, isoquinoline, pyridine, piperidine, tropane, and quinolizidine.Alkaloids are found in a wide variety of foods, such as tea, coffee, fruits and vegetables, spices, legumes, and nuts, and their distribution in the human diet varies according to geographic region and dietary habits.Furthermore, their bioavailability can be affected by several factors, such as the food matrix, the way of processing, and the intestinal microbiota, among others [21][22][23].Some of the most studied bioactive alkaloids, which are discussed in this review, are shown in Figure 2.

Saponins
Saponins are a group of chemical compounds found in a wide variety of plants that have a common steroid or triterpenoid ring structure with one or more hydroxyl groups; some of the most common saponins are ginsenoside, lupeol, and furostan (Figure 3).They can be classified into several categories, including steroids and triterpenes.These compounds are found in a wide variety of foods, including legumes, cereals, fruits, vegetables, tea, coffee, cocoa, and spices.These secondary metabolites have been studied for their anti-inflammatory, antioxidant, antitumor, antidiabetic, and antiviral properties, among

Saponins
Saponins are a group of chemical compounds found in a wide variety of plants that have a common steroid or triterpenoid ring structure with one or more hydroxyl groups; some of the most common saponins are ginsenoside, lupeol, and furostan (Figure 3).They can be classified into several categories, including steroids and triterpenes.These compounds are found in a wide variety of foods, including legumes, cereals, fruits, vegetables, tea, coffee, cocoa, and spices.These secondary metabolites have been studied for their anti-inflammatory, antioxidant, antitumor, antidiabetic, and antiviral properties, among others.Additionally, it has been shown that saponins can improve cardiovascular health, reduce the risk of chronic diseases, and improve cognitive function [24].
others.Additionally, it has been shown that saponins can improve cardiovascular health, reduce the risk of chronic diseases, and improve cognitive function [24].Terpenes are a group of secondary metabolites naturally present in plants, derived from the mevalonic acid pathway.Terpenes have also been reported in insects and marine organisms.More than 55,000 compounds have been classified as terpenes, with a variety of characteristics, functions, and applications.They have been part of folk medicine since ancient times and have also been used for perfume making, cosmetics, flavoring, and even for religious reasons.Based on the number of isoprene units present in their structure, they are classified as hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterpenes, triterpenes, tetraterpenes, and polyterpenes.They are involved in plant development, growth, and defense against biotic and abiotic stress.Terpenoids also have synergic effects with other compounds and are commonly used as administration vehicles or additives.The most common human health-related effects attributable to terpenes are anticancer, immunomodulatory, antibacterial, antiviral, neuroprotective, antioxidant, and anti-inflammatory, among others [25][26][27].In Figure 4, we can observe the structures of common terpenes that are discussed in this paper.

Relationship between Lifestyle, Oxidative Stress, and Inflammation in Overweight and Obesity
Obesity is a multifactorial chronic disease in which social, behavioral, genetic, psychological, metabolic, cellular, and molecular factors are involved.One of the main pillars contributing to the appearance of obesity is the excessive consumption of macronutrients and low energy consumption by the body.Eating habits, along with a low level of physical activity, have led to a drastic increase in obesity [1].In general, a diet high in processed foods, saturated fats, added sugars, and refined carbohydrates has been linked to an increased risk of obesity.On the other hand, a diet rich in fruits, vegetables, lean proteins, and whole grains has been linked to a lower risk of suffering from it.Likewise, research has shown that a diet high in fat and carbohydrates induces a significant increase in Terpenes are a group of secondary metabolites naturally present in plants, derived from the mevalonic acid pathway.Terpenes have also been reported in insects and marine organisms.More than 55,000 compounds have been classified as terpenes, with a variety of characteristics, functions, and applications.They have been part of folk medicine since ancient times and have also been used for perfume making, cosmetics, flavoring, and even for religious reasons.Based on the number of isoprene units present in their structure, they are classified as hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterpenes, triterpenes, tetraterpenes, and polyterpenes.They are involved in plant development, growth, and defense against biotic and abiotic stress.Terpenoids also have synergic effects with other compounds and are commonly used as administration vehicles or additives.The most common human health-related effects attributable to terpenes are anticancer, immunomodulatory, antibacterial, antiviral, neuroprotective, antioxidant, and anti-inflammatory, among others [25][26][27].In Figure 4, we can observe the structures of common terpenes that are discussed in this paper.
others.Additionally, it has been shown that saponins can improve cardiovascular health, reduce the risk of chronic diseases, and improve cognitive function [24].Terpenes are a group of secondary metabolites naturally present in plants, derived from the mevalonic acid pathway.Terpenes have also been reported in insects and marine organisms.More than 55,000 compounds have been classified as terpenes, with a variety of characteristics, functions, and applications.They have been part of folk medicine since ancient times and have also been used for perfume making, cosmetics, flavoring, and even for religious reasons.Based on the number of isoprene units present in their structure, they are classified as hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterpenes, triterpenes, tetraterpenes, and polyterpenes.They are involved in plant development, growth, and defense against biotic and abiotic stress.Terpenoids also have synergic effects with other compounds and are commonly used as administration vehicles or additives.The most common human health-related effects attributable to terpenes are anticancer, immunomodulatory, antibacterial, antiviral, neuroprotective, antioxidant, and anti-inflammatory, among others [25][26][27].In Figure 4, we can observe the structures of common terpenes that are discussed in this paper.

Relationship between Lifestyle, Oxidative Stress, and Inflammation in Overweight and Obesity
Obesity is a multifactorial chronic disease in which social, behavioral, genetic, psychological, metabolic, cellular, and molecular factors are involved.One of the main pillars contributing to the appearance of obesity is the excessive consumption of macronutrients and low energy consumption by the body.Eating habits, along with a low level of physical activity, have led to a drastic increase in obesity [1].In general, a diet high in processed foods, saturated fats, added sugars, and refined carbohydrates has been linked to an increased risk of obesity.On the other hand, a diet rich in fruits, vegetables, lean proteins, and whole grains has been linked to a lower risk of suffering from it.Likewise, research has shown that a diet high in fat and carbohydrates induces a significant increase in

Relationship between Lifestyle, Oxidative Stress, and Inflammation in Overweight and Obesity
Obesity is a multifactorial chronic disease in which social, behavioral, genetic, psychological, metabolic, cellular, and molecular factors are involved.One of the main pillars contributing to the appearance of obesity is the excessive consumption of macronutrients and low energy consumption by the body.Eating habits, along with a low level of physical activity, have led to a drastic increase in obesity [1].In general, a diet high in processed foods, saturated fats, added sugars, and refined carbohydrates has been linked to an increased risk of obesity.On the other hand, a diet rich in fruits, vegetables, lean proteins, and whole grains has been linked to a lower risk of suffering from it.Likewise, research has shown that a diet high in fat and carbohydrates induces a significant increase in oxidative stress and inflammation in people with obesity [28].The consumption of high-fat diets can generate alterations in oxygen metabolism and increase the production of reactive oxygen species (ROS).If the production of these ROS exceeds the antioxidant capacity of the cells, the oxidative stress resulting from lipid peroxidation could contribute to the development of atherosclerosis, diabetes, cardiovascular diseases, and other complications [29,30].
ROS and reactive nitrogen species (RNS) participate in various biological actions of the body, including defense against pathogenic microorganisms, which is mediated by the immune system and intracellular signaling.However, at elevated levels, they can damage DNA, lipids, and proteins, leading to tissue injury and cell death [31].To maintain adequate levels of these reactive species, the body has antioxidant compounds and enzymes to reduce their toxicity.They have naturally occurring antioxidant compounds such as glutathione and ubiquinone, as well as some proteins and enzymes that have antioxidant functions.However, in people with obesity, these antioxidant compounds are decreased, and the production of free radicals is increased, so this balance is lost [31,32].The increased production of free radicals in obesity may be due to several factors, such as excess adipose tissue, oxidation of fatty acids, excessive oxygen consumption caused by mechanical and metabolic load, accumulation of damaged cells, the type of diet that is eaten (high-fat diets can alter oxygen metabolism), and, most importantly, the damage to the mitochondria due to the leak of electrons through the respiration chain and the excess mitochondrial triglycerides, which inhibit the translocation of adenine nucleotides and promote the generation of superoxide [28].
The increase in oxidative stress in obesity causes inflammatory processes in the body since adipocytes and preadipocytes have been identified as sources of proinflammatory cytokines such as TNF-α, IL-1, and IL-6.Therefore, obesity is considered a state of chronic, low-grade inflammation.These cytokines are potent stimulators to produce reactive oxygen and nitrogen by macrophages and monocytes, so the increase in the concentration of cytokines could increase oxidative stress [28,30,33].
Hyperplasia and hypertrophy of adipocytes in the adipose tissue are important characteristics of obese patients.This results in the release of adipokines into the bloodstream, such as leptin, which acts directly on macrophages to increase phagocytic activity, and the production of proinflammatory cytokines, which exert an effect on T cells, monocytes, neutrophils, and endothelial cells.Another important adipokine is TNF-α, which activates nuclear factor κB (NF-κ B), resulting in increased expression of adhesion molecules on the surface of endothelial cells and vascular smooth muscle cells, resulting in an inflammatory state in adipose tissue.Unlike other adipokines that can be released by adipocytes, adiponectin does not increase its expression; instead, it is reduced, and since it has regulatory actions on energy homeostasis, glucose and lipid metabolism, and anti-inflammatory effects, this is a key factor in the development of complications such as insulin resistance, metabolic syndrome, hyperglycemia, and dyslipidemia [34].

Action Mechanisms of Phytochemicals against Overweight and Obesity
Nowadays, the literature provides us with several effects that are considered antiobesogenic; nonetheless, the main targets of anti-obesity compounds are lipase inhibition, regulation of adipogenesis, thermogenesis, and appetite suppression (Table 1).Some of these effects have been evaluated at a molecular level, especially those related to adipogenesis and/or adipose tissue cells' functions and homeostasis (Figure 5).[37]

Cocoa polyphenols
Decrease plasmatic levels of proinflammatory biomarkers IL-6 and MCP-1 and increase levels of adiponectin. [38]

Berberine
Increases fatty acid oxidation by activating AMPK and reduces the phosphorylation state of JNK1 and the mRNA levels of proinflammatory cytokines.Alleviates hepatic lipid accumulation and inhibits adipocyte differentiation, proliferation, and adiposity, all through downregulating galectin-3.Activates the energy metabolic sensing pathway AMPK/SIRT1 axis, increasing PPARγ deacetylation.
Antagonize dopamine receptors D1 and D2.Reduce blood lipid and glucose values and ameliorate lipid accumulation, apoptosis, and impaired migration through the activation of the LKB1/AMPK signaling pathway.Downregulate expression of proinflammatory genes IL-6, IL-1β, and TNF-α.

Lipase Inhibitors
There are various studies focused on the inhibition of lipase enzymes since they are the enzymes with a key function during the process of digestion and absorption of lipids.In this sense, pancreatic lipase is the enzyme secreted by the pancreas, which fulfills the function of hydrolyzing the ester bonds in triglycerides (TGs) to monoglycerides and fatty acids, which, when mixed with cholesterol, lysophosphatidic acid, and bile salts in the intestine, form micelles that are absorbed in the enterocytes, where TGs are resynthesized and are stored in mature adipocytes.The increase in TGs in adipocytes is associated with overweight and obesity [15,63].Therefore, inhibition of the activity of the pancreatic lipase enzyme is a key element in reducing the digestion and absorption of lipids.

Regulation of Adipogenesis
The energy imbalance between excessive caloric intake and the absence of a rise in energy expenditure leads adipocytes to undergo hyperplasia (formation of new adipocytes) and hypertrophy (increase in cell size of existing adipocytes) with an increase in adipose tissue [64,65].Adipocyte hyperplasia, known as adipogenesis, is a complex process by which preadipocytes (cells with fibroblastic morphology derived from mesenchymal cells) undergo a phase called commitment, differentiating into mature adipocytes (terminal phase) loaded with lipids [17, 66,67].In the process of adipogenesis, adipocytes undergo sequential phenotypic, functional, and morphological changes, regulated by the transcriptional cascade and signaling pathway [17,68].The nuclear receptor PPAR-γ (peroxisome proliferator-activated receptor γ) plays an important role in differentiation.During adipogenesis, CCAAT/enhancer-binding proteins (C/EBPβ/δ) stimulate C/EBPα and PPAR-γ and stimulate differentiation and induction of adipocyte-specific genes, adipocyte protein 2 (aP2), lipoprotein lipase, fatty acid synthase (FAS), and perilipin protein [17,69].The expression of the transcription factor SREBP-1 (sterol regulatory element-binding protein) also increases PPAR-γ activity in adipocyte differentiation [70].

Thermogenesis
Thermogenesis, which is the generation of heat by the body due to an external stimulus, is divided into shivering and non-shivering thermogenesis, both involved in energy homeostasis.In the thermogenesis process, brown (BAT) and white (WAT) adipose tissue are involved, mainly BAT, whose function is to transform energy into heat through mitochondrial oxidative phosphorylation and an unusual mechanism to uncouple respiration to catabolize fatty acids and glucose to increase energy expenditure [77][78][79].
During lipolysis, fatty acids are released.An active protein involved in signaling in brown adipose tissue (BAT), called thermogenin or uncoupling protein (UCP-1), prevents the production of ATP; therefore, the increase in UCP-1 expression could prevent obesity [80].On the other hand, WAT is categorized as visceral adipose tissue.Its function is to store lipids, and it has a low thermogenesis capacity; however, WAT can be converted to BAT-like cells (beige cells), a process known as browning.Therefore, browning WAT can be a target in the treatment of obesity [79,81,82].

Appetite Suppressants
The hypothalamus and brainstem are key in the control of food intake, perceiving metabolic signals to moderate eating behaviors [83].However, appetite control is a multifactorial event derived from neurological and hormonal interactions [84].Different signals converge on the hypothalamus to create a network with the gut, liver, pancreas, brainstem, and adipose tissue to modulate appetite through higher cortical centers [85].The arcuate nucleus (ARC) of the hypothalamus is considered the main appetite regulator and has neuronal subtypes.One type of neuron coexpresses orexigenic neuropeptides such as neuropeptide Y, AgRP (agouti-related peptide), and melanin-concentrating hormone; the other type of neuron expresses anorexigenic neuropeptides like pro-opiomelanocortin, cocaine, amphetamine-regulated transcript, nefastin-1, 5-HT (5-hydroxydopamine), dopamine, and norepinephrine.Appetite regulation is controlled by the activation of anorexigenic peptides and the suppression of orexigenic neuropeptides [83,85,86].
In this review, we focused on the most recent publications of secondary metabolites with reported anti-obesogenic effects, whose mechanisms have been elucidated at a

Thermogenesis
Thermogenesis, which is the generation of heat by the body due to an external stimulus, is divided into shivering and non-shivering thermogenesis, both involved in energy homeostasis.In the thermogenesis process, brown (BAT) and white (WAT) adipose tissue are involved, mainly BAT, whose function is to transform energy into heat through mitochondrial oxidative phosphorylation and an unusual mechanism to uncouple respiration to catabolize fatty acids and glucose to increase energy expenditure [77][78][79].
During lipolysis, fatty acids are released.An active protein involved in signaling in brown adipose tissue (BAT), called thermogenin or uncoupling protein (UCP-1), prevents the production of ATP; therefore, the increase in UCP-1 expression could prevent obesity [80].On the other hand, WAT is categorized as visceral adipose tissue.Its function is to store lipids, and it has a low thermogenesis capacity; however, WAT can be converted to BAT-like cells (beige cells), a process known as browning.Therefore, browning WAT can be a target in the treatment of obesity [79,81,82].

Appetite Suppressants
The hypothalamus and brainstem are key in the control of food intake, perceiving metabolic signals to moderate eating behaviors [83].However, appetite control is a multifactorial event derived from neurological and hormonal interactions [84].Different signals converge on the hypothalamus to create a network with the gut, liver, pancreas, brainstem, and adipose tissue to modulate appetite through higher cortical centers [85].The arcuate nucleus (ARC) of the hypothalamus is considered the main appetite regulator and has neuronal subtypes.One type of neuron coexpresses orexigenic neuropeptides such as neuropeptide Y, AgRP (agouti-related peptide), and melanin-concentrating hormone; the other type of neuron expresses anorexigenic neuropeptides like pro-opiomelanocortin, cocaine, amphetamine-regulated transcript, nefastin-1, 5-HT (5-hydroxydopamine), dopamine, and norepinephrine.Appetite regulation is controlled by the activation of anorexigenic peptides and the suppression of orexigenic neuropeptides [83,85,86].
In this review, we focused on the most recent publications of secondary metabolites with reported anti-obesogenic effects, whose mechanisms have been elucidated at a molecular level in vivo and in vitro and have the potential to be used in the treatment and prevention of obesity.

Polyphenols Modulating Overweight and Obesity
Polyphenols have been the focus of many studies regarding the promotion of human health.Many reports associate polyphenols with antioxidant, anti-inflammatory, and anticancer effects, protective effects against neurodegenerative diseases, and their potential as agents against overweight and obesity.Boix-Castejón, Herranz-López, Pérez Gago, Olivares-Vicente, Caturla, Roche, and Micol [35] reported that a combination of Lippia citriodora and Hibiscus sabdariffa polyphenol-rich extracts administered at 500 mg/day to 54 overweight subjects could improve anthropometric measurements like body fat and decrease blood pressure and heart rate.Also, the extracts showed increased levels of adipohormones regulating hunger and satiety and anorexigenic hormones like glucagon-like peptide-1 and decreased levels of ghrelin, an orexigenic hormone.The authors suggested that AMP-activated protein kinases may play a role in the regulation of energy homeostasis, daily energy expenditure, and lipid metabolism.A further study in obese individuals in a randomized controlled trial showed that administration of L. citriodora and H. sabdariffa extracts for 2 months improved the anthropometric parameters of body weight, body mass index, abdominal circumference, and percentage of body fat.Also, the treatment with the extracts in overweight and obese individuals reduced systolic and diastolic blood pressure during the first 30 days of treatment.Interestingly, no adverse effects were observed during the study.This effect was attributed to the most abundant compounds identified in the mixture: verbascoside, delphinidin-3-O-sambudioside, cyanidin-3-O-samudioside, and isoverbascoside.It was mentioned that the synergy of these molecules could mediate leptin levels, regulating satiety and modulating the activation of AMPK [36].Curcumin is a potent alkaloid that has shown an anti-obesity mechanism through the modulation of SIRT1/AMPK α /FOXO1 in bovine adipocytes and the modulation of UPC1 (uncoupling protein 1) in male mice with induced obesity [39].
López-Tenorio, Domínguez-López, Miliar-García, Escalona-Cardoso, Real-Sandoval, Gómez-Alcalá, and Jaramillo-Flores [37] also showed the potential synergistic action of natural products, as they showed that the combination of morin (50 mg/kg weight) and polyunsaturated fatty acids (1 mL/kg weight) (EPA and DHA, 1:1 ratio) downregulated the expression of the inflammasome biomarker Nlrp3 mRNA when administered to highfat-fed Wistar rats, as the effects of the administered bioactive components were better than each individually.Furthermore, the mixture also improved biochemical parameters like decreased levels of triacylglycerides, increased HDL cholesterol, and decreased LDL cholesterol levels.
Cocoa polyphenols have been associated with decreased levels of inflammation biomarkers in obesity.The study by Gu, Yu, and Lambert [38] administered cocoa powder to high-fat diet-fed male C57BL/6J mice.Cocoa supplementation decreased weight gain, final body weight, and insulin resistance by improving the HOMA-IR, and it decreased the severity of fatty liver disease by modulating the levels of plasma alanine aminotransferase and liver triglyceride.Furthermore, cocoa supplementation decreased the plasmatic levels of the proinflammatory biomarkers IL-6 and MCP-1 and increased the levels of adiponectin by 33.6%, which was associated with the modulation of the gene expression of these proteins.
Resveratrol is one of the most studied phytochemicals regarding its bioactive effects in humans, aimed at improving health or preventing diseases, including overweight, obesity, and their complications.In this section, we focus on the most recent publications.A systematic review of clinical trials using resveratrol in adult obese patients concluded that this compound showed effects such as weight loss promotion, waist circumference reduction, body mass index reduction, lean mass increase, and fat mass decrease.It has also been reported that results regarding the effects of resveratrol in obese patients present significant heterogeneity in trial design; thus, conclusions are considered inconsistent [86,87].

Alkaloids Modulating Overweight and Obesity
Alkaloids have been reported to have a variety of pharmacological activities, including antibacterial, antidepressant, antihistaminic, anticancer, and fungicidal, among others.Some alkaloids discovered in natural sources are used as modern drugs nowadays [88,89].Recently, alkaloids have been related to obesity, overweight, and their complications.During the past decade, along with polyphenols, alkaloids have been highly reported for their anti-obesogenic effects at a molecular level due to their structure, which makes it easy to interact with molecules and receptors, especially those of the nervous system.Their effects have been evaluated in vitro and in vivo, and in several cases, mechanisms are determined at a molecular level: adipogenesis modulation, adipocyte differentiation, lipogenesis, lipolysis, fatty acid oxidation, oxidative stress and inflammation caused by obesity, and others [90].Due to the vast amount of information available about the molecular mechanisms of alkaloids, we aimed to cite the most recent and novel articles.
The molecule bouchardatine, an alkaloid isolated from the Bouchardatia neurococca plant, has shown interesting results regarding obesity.In 2017, a group of researchers [40] evaluated bouchardatine in 3T3-L1 cells (adipocytes) and in mice fed with a high-fat diet.The results indicated that, in adipocytes, this alkaloid facilitates activation of AMPK by increasing sirtuin 1 (SIRT1) activity to contribute to liver kinase B1 (LKB1) activating AMPK and reducing lipid accumulation inside the cells.Additionally, in obese mice with chronic administration of bouchardatine (50 mg/kg), activation of the SIRT1-LKB1-AMPK pathway was determined, leading to attenuation of weight gain, dyslipidemia, and fatty liver.All these results in vivo were reported without any side effects or changes in food intake.
Morus alba L. is a source of alkaloids (1-deoxynojirimycin, 1,4-dideoxy-1,4-imino-Darabinitol, and fagomin), and it is already being used in China as a treatment for type 2 diabetes mellitus.To elucidate the molecular mechanisms of these alkaloids, researchers administered Morus alba L. powder to mice with fatty livers.The alkaloids significantly increased the expression and secretion of adiponectin, both in mice and in 3T3L-1 cells.Several genes (436) were evaluated in the liver tissue of mice treated with alkaloids; the top 20 genes exhibited upregulation and downregulation effects, including a reduction in the expression of lipid uptake genes (CD36), proinflammatory genes (C-X-C motif chemokine ligand 9 (Cxcl9)), and interferon alpha-inducible protein 27-like protein 2A (Ifi27l2a).Another finding indicates that the mRNA levels of adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2) were significantly higher compared to the control group of mice.In addition, the expression of the lipogenic gene PPARγ was significantly downregulated at a dose of 400 mg/kg.Morus alba L. alkaloids were an effective treatment for the activation of AMPK and the upregulation of PPARα and PGC1α expression to help improve β-oxidation of fatty acids.These findings imply that genes and pathways of lipid metabolism and metabolic stress-induced liver injury in obese mice are regulated by alkaloids [41].
Berberine is one of the most reported alkaloids regarding its anti-obesogenic effects.It is an isoquinoline alkaloid, extracted from plants of the Coptis and Phellodendron genera [42].This compound is capable of increasing fatty acid oxidation by activating AMPK in hepatic cell lines (HepG2), and in the liver and adipose tissue of mice with obesity-associated non-alcoholic fatty liver disease, it shows a reduction in the phosphorylation state of JNK1 and the mRNA levels of proinflammatory cytokines [43].It has also been reported as an alleviator of adipogenesis in 3T3-L1 cell lines via regulation of the AMPKα-SREBP pathway [44].It also increases the ATP-binding cassette transporter, which mediates hepatic cholesterol and modulates protein kinase C phosphorylation on Tyr311, alleviating hepatic lipid accumulation [45].In mouse white adipose tissue, berberine inhibited adipocyte differentiation, proliferation, and adiposity, all through downregulating galectin-3 [46].In male mice fed with a high-fat diet, berberine (25 mg/kg and 100 mg/kg) activates the energy metabolic sensing pathway AMPK/SIRT1 axis, increasing PPARγ deacetylation, finally leading to the remodeling of the adipose tissue and a significant increase in the thermogenic protein UCP-1 [47].Recently, berberine has shown a novel anti-obesogenic effect: When administered orally to obese mice, it binds to the bitter-taste receptors present in the intestine (TAS2Rs).By signaling the TAS2Rs pathway, berberine upregulates the release of GLP-1 and helps ameliorate obesity [91].
In a different approach, eight alkaloids present in lotus (Nelumbo nucifera Gaertn.)leaves were evaluated as dopamine receptor (D1 and D2) antagonists in kidney cells (human embryonic kidney 239 cell lines).Antagonizing these receptors is a strategy that has recently been proven to be effective in the long-term maintenance of weight loss.Among the alkaloids tested, o-nornuciferine was the most potent as a dopamine inhibitor.This is an aporphine alkaloid, which means it has an extra ring connecting a tetrahydroisoquinoline and a benzyl.Analyzing o-nornuciferine, it was determined that R3 was the critical pharmacophore and that methyl substation was preferred to hydrogen at this position.In addition, this alkaloid is capable of fully desensitizing serotonin 2A by antagonizing the 5-HT2A receptor [48].Also extracted from lotus leaves, the aporphine alkaloid nuciferine has been widely studied due to its anti-obesogenic effects, such as lowering blood lipid and glucose values and reducing inflammation [49].One of the most recent publications determined that this molecule ameliorates lipid accumulation, apoptosis, and impaired migration through the activation of the LKB1/AMPK signaling pathway, thus reducing the lipotoxicity related to overweight and obesity [50].And in mice fed a high-fat diet, it improves microbiome dysbiosis and downregulates the expression of proinflammatory genes IL-6, IL-1β, and TNF-α [51].
Other alkaloids have been reported to affect a variety of molecular mechanisms related to obesity, adipogenesis, lipogenesis, oxidative stress, and inflammation related to obesity.For example, evodiamine is capable of lowering oxidative stress and inflammation caused by free fatty acids by inhibiting enhanced expression of P2X 7 and its dependent TNF-α expression and ERK 1/2 phosphorylation [52].Betaine administered to mice with hepatic steatosis resulted in a significant activation of AMPK and downregulation of sterol regulatory element-binding protein 1C (SREBP-1c), enhancing lipid metabolism [53].
The structure relationship between most of these alkaloids and their molecular mechanisms against obesity has been discussed and is mainly attributed to the alkoxyl at the C1 position, the hydroxyl at the C2 position, and the alkyl substituent on the N-atom.Also, the lack of a methyl group in the R1 and R3 positions has been mentioned as an important factor in their effectiveness.Although it is important to mention that the low bioavailability, absorption, and water solubility of alkaloids are some important factors to consider for their application, this implies that micro-or nano-encapsulation is a convenient future solution for their administration [92][93][94].

Saponins Modulating Overweight and Obesity
Even though saponins are known for their anti-obesogenic effects as inhibitors of lipid digestion and absorption at the intestinal level, there are other effects and mechanisms of these molecules in different cells or tissues, such as adipose and hepatic tissues, which are key organs involved in obesity development.
Bupleurum chinensis is a plant whose root has been used to treat inflammation, fever, and liver diseases but also against lipid accumulation.The mechanism linked to its antiobesogenic activity was determined by isolating two saponins, saikosaponin A and saikosaponin D, and evaluating their effect on adipocytes (3T3-L1 cells).The results indicated that, in doses that do not compromise cell viability, these two saponins suppress the expression of adipogenic genes such as peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), sterol regulatory elementbinding protein-1c (SREBP-1c), and adiponectin.They also downregulate the expression of lipogenic genes such as fatty acid-binding protein (FABP4), fatty acid synthase (FAS), and lipoprotein lipase (LPL) [54].
A saponin-rich fraction obtained from green tea seeds was used to design a formulation with glucosides extracted from Stevia rebaudiana (stevia) and evaluated in 3T3-L1 cells.The combination showed synergistic behavior and significantly inhibited the expression of adipogenesis-and lipogenesis-related genes and signaling molecules, including PPARγ, C/EBPα, aP2, and SREBP-1c (sterol regulatory element-binding protein) [55].
Ginsenoside Rg2 was extracted from red ginger to be used as a treatment in obese mice and in 3T3-L1 cells to elucidate the anti-obesogenic mechanism of this saponin.Both in vivo and in vitro, Ginsenoside Rg2 induced the activation of AMPK, subsequently decreasing the expression of adipogenic transcription factors (PPARγ, C/EBPα, and SREBP1-c) [95].Similar research was conducted using only saponins extracted from the roots of ginseng and tested on obese mice with induced non-alcoholic fatty liver disease.Anti-inflammatory activity was observed in the mice's liver tissue, modulating the expression of the inflammatory cytokines ARG1 (arginase), CCL2, and IL-1β.
Soy saponins were administered to mice and used as a treatment in 3T3-L1 cells.The results indicated that these compounds are involved in the reduction in triacylglycerol accumulation and lipogenesis in adipose cells.While some saponins have demonstrated that their anti-obesogenic mechanism is linked to the downregulation of adipogenesis, soy saponins have an effect on lipogenesis, significantly downregulating SREBP-1c and fatty acid synthase (FAS) [57].
Other molecular mechanisms were reported in 2019.Gynostemma pentaphyllum is a plant used in traditional medicine to treat diabetes mellitus, dyslipidemia, and inflammation.It was demonstrated that, among other mechanisms, the saponins present in its extract were able to significantly decrease the expression of adipocyte protein 2 (AP2) and sirtuin 1 (SIRT1).They also increased the expression of carnitine palmitoyltransferase (CPT1) and hormone-sensitive lipase (HSL), thus contributing to ameliorating obesity in male mice [58].
A clinical trial was conducted using a Gynostemma pentaphyllum extract rich in the saponin Damulin A. Its effects were evaluated in obese men and women and compared with a placebo group, concluding that a 12-week supplementation of this compound significantly decreased total abdominal fat, body weight, fat mass, body fat percentage, and BMI (body mass index).This supplementation caused no side effects on the individuals [96].
It has been determined that the primary structure-activity relationship for saponin effects is the ether bond between carbon 13 (C-13) and carbon 28 (C-28).Other structural factors for their bioactive effects are the number of sugars in the carbon 3 position and the aglycone structure, which may confer saponins with the ability to interact with nuclear factors related to ameliorating obesity [97,98].

Terpenes Modulating Overweight and Obesity
Terpenes are a very extensive group of secondary metabolites with proven antiobesogenic effects [98].Previously, it was reported that terpenes from plants exert action as modulators of receptors involved in the metabolism of lipids, such as PPARs and LXRs (liver X receptors) [99].PPARs, as mentioned above, are strongly involved in the adipogenesis process through the expression of FABP4, AP2, adiponectin, LPL, phosphoenolpyruvate carboxykinase (PEPCK), and glucose transporter type 4 (GLUT4).LXRs participate in the expression of genes involved in the effluence of cholesterol on HDL particles through regulation of ATP-binding cassette transporters (ABCA1, ABCG5, and ABCG8), as well as in genes involved in the transport and elimination of cholesterol; thus, LXRs are very important in cholesterol metabolism [100].Therefore, several plant species have been studied in order to identify their natural components, such as terpenes or their derivatives, and to understand their anti-obesogenic mechanisms to identify possible targets for obesity treatment [101].
Terpenes from Ilex aquifolium have been studied in order to understand their antiobesity mechanism.Pachura et al. [60] evaluated the effect of the terpenoid fraction of extracts from I. aquifolium leaves on the expression of genes related to lipid metabolism and on the hepatic architecture using obese Zucker male rats as an in vivo model.Firstly, the composition of I. aquifolium leaves was analyzed, and the monoterpenes p-cymene, αphellandrene, and α-pinene, as well as the triterpenes oleanolic acid and ursolic acid, were found.Secondly, the rats were fed 10 mg of terpenoid fraction per kg of body weight during eight weeks and compared with the obese control group.The rats fed with the terpenoid fraction showed a significant increase in the expression of the gene LXR1 (liver X receptor) factor, which is required for the elimination of cholesterol in mice [59].Furthermore, intake of terpenoids from I. aquifolium reduced the accumulation of lipids in the liver, as compared with the obese rats in the control group.Additionally, the terpenes of this plant species exerted antioxidant and anti-inflammatory effects.This evidence indicates that the terpenes found in the leaves of Ilex aquifolium have potential as lipid metabolism modulators and could be used as an alternative in obesity treatment.
Another plant species recently studied is Brucea javanica.Lahrita et al. [61] evaluated the pro-lipolytic effect of terpenes, known as quassinoids, found in extracts from B. javanica fruit using 3T3-L1 cells differentiated to adipocytes as an in vitro model.The extracts from the fruit contained the terpenes brucein A-C, brusatol, bruceantinol, hydroxybrucein A, and yadanzioside B. The 3T3-L1 adipocytes were treated with the extracts at concentrations of 3.13-100 µg/mL for 24 h, and the glycerol released was measured as a lipolysis marker.All concentrations evaluated significantly increased glycerol levels compared with the control.Furthermore, individual terpenes from the extract were evaluated, and it was found that yadanzioside B (1-100 µM) did not significantly affect glycerol levels.On the other hand, the rest of the terpenes, brucein A-C, brusatol, bruceantinol, and hydroxybrucein A, exerted pro-lipolytic activity in the cells with a dose-dependent effect (0.16-10 µM), and bruceantinol showed the highest lipolytic activity.According to the authors, the presence of a hydroxyl group in position 3, as well as short acyl chains esterified to the hydroxyl in position 15, may be of relevance for the pro-lipolytic activity of these terpenes.This demonstrates the potential of quassinoids from B. javanica in the treatment of obesity.
In addition to plants, other natural products containing terpenes, such as marine resources, have been explored for their anti-obesogenic properties; such is the case of soft corals of the order Alcyonacea [61].In this study, the effect of methanolic extract of Sarcophyton glaucum supplementation on several obesity markers was studied in obese rats.Obese male albino rats fed crude methanolic extract of S. glaucum (20 mg/kg) during eight weeks showed lower levels of fasting blood sugar, HOMA-IR (homeostatic model assessment for insulin resistance), cholesterol, triglycerides, and LDL cholesterol and higher levels of insulin and HDL cholesterol when compared with the obese control group (without S. glaucum extract supplementation).Furthermore, levels of fetuin A, fetuin B, and PTP1B (protein tyrosine phosphatase 1B) were significantly reduced, while adropin and omentin levels increased in the serum of rats fed the extract compared with the control group.Fetuin A is known for participating as an inhibitor of the lysis of lipids, which causes the accumulation of triglycerides in the liver and might alter adipogenesis.On the other hand, PTP1B contributes to insulin resistance.Also, the treatment of obese rats with the extract increased the expression of PPARγ coactivator 1 alpha.The regulation of these markers is promising as a target for the treatment of obesity.A total of 27 terpenoids were identified in the methanolic extract of S. glaucum, of which 2 showed the highest anti-obesogenic potential: 1 tricyclic diterpene and 1 bicyclic diterpene with cores II and III, respectively.These diterpenes shared an α, β-unsaturated ε-caprolactone fused to a cyclic system in their structures, which might be important for their activity.
Terpenes and other natural products show potential as therapeutic agents against obesity due to their capacity to modulate diverse markers related to lipid and glucose metabolism.

Conclusions and Perspectives
Understanding the mechanisms of action and safe dosage of plants, fruits, extracts, compounds, or any type of nutraceutical is an essential step in designing effective nutraceuticals and biopharmaceuticals.This information can also help to determine when it is safe to use them, whether it is a matter of age or health condition.It can also be useful when deciding if using them as co-adjuvants or for prevention could result in antagonism with other treatments that the individual is already receiving.On the other hand, analyzing all this recent information has led us to understand the importance of evaluating the bioaccesibility and bioavailability of anti-obesogenic compounds.Evaluating these two important factors can help determine the best way to administer them, whether as part of the diet or using the idoneous encapsulation model.Even though clinical trials have been conducted to evaluate natural products against obesity, it is a challenge to attribute anti-obesity effects to one type of compound, mainly because these trials use a pool of compounds of different structures.Some of the effects observed are attributed to the synergistic effects between groups of compounds such as alkaloids and phenolic acids.
Considering obesity is now considered an epidemic and that not all people have access to the drugs available on the market, having other options or co-adjuvants is crucial, especially considering that the anti-obesogenic effects of natural compounds have not yet shown side effects in in vivo evaluations.Considering the increasing prevalence of obesity around the world, the economic burden of this disease, and the number of deaths caused by it, it can be concluded that there is still a lot of work to do regarding its treatment and prevention.Available drugs can produce side effects, have negative interactions or contradictions with other pharmacological treatments, and be unavailable for low-income patients.For these reasons, natural products may be a safe adjuvant option; functional foods, nutraceutical products, extracts, and herbs can be easier to access than medication and can be easily added to an adequate diet for overweight and obese patients.

Receptors 2024, 3 , 19 Figure 5 .
Figure 5. Schematic adipogenesis process.A cascade of transcription factors is activated to induce or inhibit the expression of PPAR-γ and C/EBPα, which are the key proteins in adipogenesis.Black narrow indicates induction, and red arrow indicates inhibition.

Figure 5 .
Figure 5. Schematic adipogenesis process.A cascade of transcription factors is activated to induce or inhibit the expression of PPAR-γ and C/EBPα, which are the key proteins in adipogenesis.Black narrow indicates induction, and red arrow indicates inhibition.