Metabolic regulation of obesity by naturally occurring compounds: mechanisms and therapeutic potential

For research published between January 2000 and April 2024, a comprehensive literature search was conducted using the electronic databases PubMed, Scopus, Web of Science, and Google Scholar. The key terms and their Boolean combinations were "natural compounds" OR "bioactive compounds", "obesity" OR "anti-obesity", "adipogenesis" OR "lipolysis" OR "thermogenesis", "polyphenols" OR "alkaloids" OR "carotenoids", "green tea catechins" OR "EGCG" OR "resveratrol" OR "berberine" OR "fucoxanthin", "gut microbiota" OR "microbiome modulation", "drug delivery" OR "nanoencapsulation" OR "phospholipid complexes". Only articles in the English language were taken into account. To further find important materials, the reference lists of chosen research and pertinent review articles were also manually screened (Figure 1).

Original research presenting clinical data on the anti-obesity properties of natural substances in humans, animals, or in vitro models was one of the study's inclusion criteria. Additionally taken into consideration were studies that clarified the molecular mechanisms of action, such as those involving the AMPK, PPARγ, and UCP1 pathways. Relevant reviews and meta-analyses that concentrated on distribution strategies or treatment results were also incorporated. On the other hand, the exclusion criteria excluded studies that focused exclusively on synthetic compounds, editorials and commentaries that were not subjected to peer review, and articles that lacked mechanistic insights.

Data from the chosen articles were methodically taken out and arranged by the class and source of natural compounds, including carotenoids, polyphenols, and alkaloids. There was also documentation of the experimental models used, which included clinical trials, animal models, and cell lines. Alongside the reported results, such as changes in body weight, fat mass, and metabolic parameters, mechanisms of action were identified, including the inhibition of adipogenesis, stimulation of thermogenesis, and modulation of gut microbiota. Additionally mentioned were delivery methods such as nano formulations and improvements in bioavailability. In order to identify convergent biological pathways and evaluate their translational potential, the synthesis combines qualitative and mechanistic findings. Clinical efficacy results were compiled where appropriate to highlight the natural compounds' therapeutic value.

The prime focus in this area for the review is given on two important mechanisms like adipogenesis and lipogenesis.

The various mechanisms, when discussed, can take on the role of an enzyme.

The following descriptions provide a detailed overview on the role of natural anti-obesity compounds that often inhibit key enzymes involved in adipogenesis (fat cell formation) and lipogenesis (fat synthesis). The key targets include the following:

The following path can be discussed to explain the role of FAS. Obesity results from excessive fat accumulation due to dysregulated adipogenesis (formation of new fat cells) and lipogenesis (synthesis of fatty acids) (6).

Naturally occurring compounds target these processes through multiple mechanisms, namely:

Lipogenesis involves de novo fatty acid synthesis, primarily in liver and adipose tissue. The key targets discussed in the following Tables 1 and 2 describe the role of enzymes and natural compounds.

Table 1 elaborates on the mechanism behind different metabolic reactions employing enzymes, which acts on natural inhibitors and promote the therapeutic insights by different mechanisms as cited in different research reports, respectively. The relatively underexplored challenges and delivery strategies for the clinical translation of curcumin and resveratrol have been addressed, with support from select literature reports. Key challenges include poor bioavailability, as both compounds exhibit low solubility, rapid metabolism, and fast systemic clearance, which collectively limit their therapeutic efficacy (11, 12). Chemical instability further hampers their potential, with curcumin degrading at physiological pH and resveratrol undergoing oxidation and isomerization (13). Additionally, dose-limiting toxicity has been reported, wherein high doses of resveratrol may induce gastrointestinal distress and excessive curcumin intake may lead to hepatotoxicity (14).

Several delivery approaches have been developed to overcome these barriers. Nanocarriers, such as liposomes, polymeric nanoparticles, and micelles, improve solubility and prolong systemic circulation (15, 16). Phospholipid complexes—for instance, Meriva^® for curcumin—enhance intestinal absorption (17). PEGylation and cyclodextrin inclusion increase stability and bioavailability (18), while prodrugs and chemical conjugates reduce metabolic degradation (19). Optimizing these delivery strategies is essential to fully harness the therapeutic potential of curcumin and resveratrol in clinical settings. Table 2 presents the data for natural compounds employed in modulating hormone actions and influencing the mechanisms as described in various research reports.

Another mechanism for controlling transcriptional events will also be discussed as follows where the role of various compounds in genetic and physiological regulations as well metabolism is also described.

The various control mechanisms are reviewed in research reports, and a few representative ones are stated here—for example, sterol regulatory element-binding protein 1c (SREBP-1c) and master regulator of lipogenic genes (ACC, FAS); Omega-3s (EPA/DHA) promote SREBP-1c proteasomal degradation. Another mechanism in fat storage is also described, like combined effects on fat storage. The various natural compounds often exhibit dual inhibition—for example, fucoxanthin (brown seaweed)↓ (downregulation) PPARγ and ↑ (upregulation) AMPK (leads to or results in) → reduces lipid droplet size by 60% in human adipocytes. The recent literature survey also enlightens in the section "Clinical Implications and Challenges" in research on the gap of the avenue to be explored in later stages in a similar line of action. They are as detailed in the following discussion.

While single compounds show efficacy, combinations (e.g., resveratrol + quercetin) require dose optimization to avoid antagonism. Facets on sex differences are also studied in this research. PPARγ inhibition is 23% more effective in female adipocytes. Despite the growing recognition of sex-based differences in PPARγ inhibition, several key challenges hinder progress in this field. First, biological complexity makes it difficult to isolate hormonal effects from other sex-specific factors, as estrogen's interaction with PPARγ is influenced by metabolic, genetic, and epigenetic variables (20). Second, historical bias in preclinical and clinical research—particularly the underrepresentation of female subjects in early drug development—has led to a lack of sex-disaggregated data, obscuring true efficacy and safety differences (21). Third, hormonal variability in females (e.g., menstrual cycles, menopause, pregnancy) complicates the standardization of dosing regimens, raising concerns about treatment consistency (22). Additionally, regulatory and cultural barriers persist, as sex-specific drug development remains underprioritized due to higher costs and logistical challenges in trial design. Addressing these issues requires a multidisciplinary approach, including mandatory sex-balanced trials, advanced hormone-modulated delivery systems, and translational studies to bridge preclinical findings with clinical outcomes.

Nanoparticle-encapsulated EGCG improves adipose targeting by fourfold. A consolidated overview of the mechanism of action mediated by natural compounds to combat obesity issues is shown in Table 3. The tables also aims to focus on compounds that act on different obesity problems by targeting specific metabolic systems and key enzymes so that the target specific therapy or natural inhibition can be initiated. The focus should be on energy balance toward fat utilization rather than storage.

Natural compounds also enhance lipid breakdown by the following mechanism of targets:

A brief insight on the detailed mechanism has been elaborated as follows: activation of PPARα and PGC-1α increases mitochondrial fatty acid oxidation. Compounds like curcumin and omega-3s enhance these pathways' shifting.

Target enzymes/proteins: The listed target enzymes/proteins play an important role in metabolic functions and inhibitory mechanisms, like HSL (hormone-sensitive lipase) and ATGL (adipose triglyceride lipase) which play a prominent role in the hydrolysis of triglycerides into free fatty acids.

Natural activators with their roles are enlisted as follow: capsaicin (chili peppers)–stimulates catecholamine release, activating HSL (32). Berberine (golden seal) upregulates AMPK, enhancing lipolysis (33). UCP1 (uncoupling protein 1): this important protein plays a vital role in mediating thermogenesis in brown adipose tissue (BAT). Natural inducers like common dietary and daily commodity things are also utilized as in the following examples: ginsenosides (ginseng)—activate UCP1 via SIRT1/PGC-1α pathway; caffeine (coffee, tea) —enhances BAT activity via β-adrenergic stimulation (34). Appetite regulation and satiety enhancement: In this regard, few important pathways were shared to understand the role of a few natural compounds.

Leptin and ghrelin signaling: Leptin suppresses appetite (35), while ghrelin stimulates hunger.

Natural modulators: Various natural modulators can be effective in playing a significant role, and a few of them are described in detail as follows:

Fucoxanthin (brown seaweed)—This compound increases adiponectin, improving leptin sensitivity. Fiber (e.g., β-glucan, glucomannan), like compounds, delay gastric emptying, reducing ghrelin secretion. Likewise in the case of serotonin (5-HT) and dopamine pathways, the regulation of mood and food cravings was being observed. The natural modulators play a significant role by the following manner—for example, 5-HTP (Griffonia simplicifolia), a precursor to serotonin, reduces emotional eating, while L-theanine (green tea) used to modulate dopamine and decreases reward-driven eating.

Natural compounds, such as polyphenols (36), dietary fibers (37), and plant-derived bioactive molecules, modulate the gut microbiome to combat obesity through multiple mechanisms. These compounds enhance beneficial bacteria (e.g., Akkermansia muciniphila, Bifidobacterium spp.) while suppressing obesity-linked microbes (e.g., Firmicutes). They promote the production of short-chain fatty acids (SCFAs) like butyrate, which improve insulin sensitivity, reduce inflammation, and enhance satiety. Additionally, natural compounds inhibit endotoxin-producing bacteria, lowering metabolic endotoxemia and adipose tissue inflammation. By restoring microbial balance and improving gut barrier integrity, these bioactive molecules help regulate lipid metabolism and energy expenditure, offering a promising dietary strategy for obesity management through microbiome-targeted interventions. Emerging evidence highlights the crucial role of gut microbiota in modulating the efficacy of bioactive compounds through species-specific metabolic transformations. Studies demonstrate that gut bacteria convert compounds like curcumin and resveratrol into active metabolites (38, 39), while microbial-derived short-chain fatty acids influence host targets like PPARγ (40). The microbiome also affects drug bioavailability, with significant interpersonal variability observed (41). Specific bacterial taxa are implicated in polyphenol activation (42), and gnotobiotic models confirm causal relationships. However, establishing definitive microbe–compound interactions requires further mechanistic studies accounting for individual microbiome variations and standardized intervention protocols. These findings underscore the microbiome's potential as a modifier of therapeutic outcomes. The mechanism will be described in the following discussion.

The various pathways as mentioned below (Figure 2) were taken as examples where natural compounds play an important role by specific mechanisms.

Short-chain fatty acid (SCFA) production plays a beneficial role in butyrate, propionate, and acetate to improve insulin sensitivity and reduce inflammation (43). There are few natural prebiotics like inulin and oligofructose (chicory root, garlic) which promote SCFA-producing bacteria (e.g., Bifidobacterium spp.). In bile acid metabolism, the bile acids also activate FXR and TGR5 receptors, influencing lipid metabolism (44). The few detailed natural modulators as exemplified here, like chitosan (crustacean shells), are used to bind bile acids, reducing fat absorption. Many such examples can likewise be explored in this regard.

Current research underscores the significant role of plant-derived bioactive compounds in combating obesity through microbiome regulation and multi-system mechanisms as shown in Table 4. Clinical trials reveal that polyphenolic compounds, particularly resveratrol (500 mg daily) and green tea catechins (300–400 mg daily), effectively boost the populations of beneficial gut bacteria (Akkermansia and Bifidobacterium), resulting in improved metabolic function and measurable fat reduction (4% to 5% decrease) (45). The plant alkaloid berberine (500 mg three times daily) demonstrates remarkable efficacy in rebalancing gut flora and stimulating metabolic regulators. Dietary fiber interventions (15 g/day) promote the growth of beneficial microbes (Roseburia and Faecalibacterium), correlating with a significant weight reduction (6.2%). Curcumin formulations (1 g/day) exhibit novel effects on appetite regulation through gut–brain communication pathways. These natural agents operate through multiple biological pathways, influencing metabolic signaling, inflammatory responses, and energy regulation. The latest clinical guidelines advocate for customized treatment approaches combining these compounds with probiotics. While showing great promise, further research is required to establish optimal treatment protocols and verify long-term benefits. Advanced microbiome analysis now facilitates tailored therapeutic strategies, positioning these natural solutions as innovative options in obesity care.

With a focus on appetite regulation and the microbiome, Figure 3 depicts the role of probiotics and a number of plant bioactive in the treatment of obesity. It highlights certain natural substances that have been shown in scientific studies to have anti-obesity effects: berberine (500 mg three times a day), curcumin (1 g daily), green tea catechins (300–400 mg daily), and resveratrol (500 mg daily). Probiotics (15 g/day) are also included because of their beneficial effects on gut health (18, 47, 49, 50). By supporting good gut flora like Akkermansia and Bifidobacterium, which have been shown to have a positive effect on inflammation and metabolic health, these bioactives help people manage their weight. These drugs promote improvements in gut microbiota that result in better treatment outcomes through mechanisms involving multi-system effects, metabolic regulation, inflammatory response reduction, and appetite control. According to the figure, clinically, these interventions can result in 4% to 5% decrease in body fat and 6.2% decrease in total weight. Combining probiotics and plant bioactives offers a promising, multifaceted strategy to manage obesity that supports energy regulation and individualized care based on the makeup of the gut microbiota (49, 50).

Many natural compounds (e.g., curcumin, resveratrol) suffer from poor absorption. The probable solutions are nanoencapsulation and phospholipid complexes (e.g., phytosomes). Even studies on synergistic combinations—for example, green tea extract (EGCG + caffeine)—show better efficacy than single compounds.

This refers to the sector of personalized interventions based on gut microbiome profiling and genetic polymorphisms (e.g., FTO gene variants). In vivo studies investigating natural compounds for obesity-related disorders reveal complex interactions. Various compounds often work synergistically, where their combined effect is greater than the sum of individual effects, offering multi-targeted approaches to combat obesity (51)—for instance, combinations of polyphenols like epigallocatechin-3-gallate (EGCG) and caffeine have shown enhanced anti-obesity synergy by modulating gut microbiota and bile acid metabolism (52). Conversely, antagonistic interactions can occur, where one compound diminishes the efficacy of another, potentially compromising therapeutic outcomes. Understanding these intricate dynamics is crucial for developing effective and safe natural product-based strategies for obesity management.