Metabolic disorders involve multiple abnormalities, including insulin resistance, dysregulated glucose and lipid metabolism, chronic inflammation, and oxidative stress. Natural products possess diverse structural classes and molecular targets and can improve metabolic homeostasis by regulating insulin signaling, glucose and lipid synthesis, fatty acid oxidation, metabolic inflammation, and the brain-gut axis. They provide an important foundation for mechanistic studies of metabolic diseases and the development of lead compounds.

Keywords: natural products; metabolic disorders; insulin resistance; lipid metabolism; metabolic inflammation; oxidative stress; SREBP; AMPK; NLRP3; brain-gut axis

1 Pathological Basis of Metabolic Disorders

1.1 Major Manifestations of Metabolic Disorders

Metabolic disorders comprise a group of pathological conditions caused by imbalances in energy intake, storage, and utilization. They may manifest as obesity, insulin resistance, hyperglycemia, dyslipidemia, fatty liver, and hypertension and may further progress to type 2 diabetes, atherosclerotic cardiovascular disease, and metabolic dysfunction-associated steatotic liver disease. Their development does not result from dysfunction of a single metabolic pathway but from coordinated disturbances involving the liver, skeletal muscle, adipose tissue, pancreatic islets, intestine, and central nervous system.

Figure 1 Major manifestations of metabolic disorders and associated disease risks

1.2 Insulin Resistance

Insulin resistance is a common pathological basis of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and related conditions. Under normal conditions, insulin promotes glucose uptake in skeletal muscle and adipose tissue and suppresses hepatic gluconeogenesis through signaling involving the insulin receptor, insulin receptor substrates, PI3K, and AKT. Diacylglycerol accumulation, activation of inflammatory kinases, negative regulation of insulin signaling, and mitochondrial dysfunction can impair this pathway, resulting in reduced glucose uptake, increased hepatic glucose output, and compensatory hyperinsulinemia.

1.3 Dysregulation of Glucose and Lipid Metabolism

The synthesis and breakdown of fatty acids, triglycerides, and cholesterol are regulated by transcriptional networks involving sterol regulatory element-binding proteins (SREBPs), liver X receptor α, and peroxisome proliferator-activated receptors. Nutrient excess can promote SREBP maturation and lipogenesis, thereby increasing hepatic triglycerides, very-low-density lipoprotein production, and ectopic lipid deposition. Lipid intermediates such as diacylglycerols and ceramides can further suppress insulin signaling, generating a positive-feedback loop that aggravates glucose and lipid metabolic dysregulation.

1.4 Metabolic Inflammation

Obesity, type 2 diabetes, atherosclerosis, and metabolic dysfunction-associated steatotic liver disease are commonly accompanied by chronic low-grade inflammation. Metabolism-associated danger signals, including free fatty acids, oxidized low-density lipoprotein, glucose, advanced glycation end products, and cholesterol crystals, can activate pattern-recognition receptors, NF-κB, MAPK, and the NLRP3 inflammasome, promoting the release of inflammatory cytokines such as IL-1β, IL-6, and TNF-α. Inflammatory signaling can also interfere with insulin receptor substrate and AKT activation, further aggravating insulin resistance.

1.5 Oxidative Stress

Reactive oxygen species such as superoxide anions and hydrogen peroxide are generated during mitochondrial electron transport. Under normal conditions, antioxidant systems including superoxide dismutase, catalase, glutathione peroxidase, thioredoxin, and reduced glutathione maintain redox balance. When reactive oxygen species production exceeds cellular clearance capacity, lipid peroxidation, protein oxidation, DNA damage, and mitochondrial dysfunction can occur, further amplifying inflammation and metabolic abnormalities.

Table 1 Major Pathological Processes in Metabolic Disorders

2 Natural Products That Restore Insulin Signaling

2.1 Atractylenolide II and DGKQ

Atractylenolide II can act on diacylglycerol kinase theta (DGKQ). DGKQ converts diacylglycerol into phosphatidic acid, thereby reducing intracellular diacylglycerol levels. Excess diacylglycerol can activate protein kinase Cε and related molecules and suppress insulin signaling. Activation of DGKQ may therefore improve lipid-intermediate-induced insulin resistance. Relevant studies should simultaneously assess diacylglycerol levels, PKCε activation, insulin receptor signaling, and glucose uptake.

2.2 Gentiopicroside and PAQR3

Progestin and adipoQ receptor family member 3 (PAQR3) can negatively regulate insulin signaling. By suppressing PAQR3-associated activity, Gentiopicroside may restore signaling downstream of the insulin receptor and improve glucose utilization. Evaluation of this mechanism should combine PAQR3-expression intervention with measurements of AKT phosphorylation, GLUT4 translocation, and glucose uptake.

2.3 S-Allylmercaptocysteine and INSR

S-Allylmercaptocysteine can regulate insulin receptor (INSR)-associated signaling and promote activation of the IRS, PI3K, and AKT pathways. Studies can focus on INSR binding and phosphorylation, glycogen synthesis, GLUT4 translocation, and cellular glucose uptake. Receptor inhibition or genetic intervention should be used to verify whether its effects depend on INSR.

3 Natural Products That Inhibit Glucose and Lipid Synthesis

3.1 Betulin and SCAP/SREBP

SREBP precursors are located in the endoplasmic reticulum membrane and form complexes with SREBP cleavage-activating protein (SCAP). Changes in nutrient and cholesterol status promote transport of the SCAP-SREBP complex, allowing SREBP to undergo proteolytic processing and generate a transcriptionally active nuclear fragment. Betulin can inhibit SCAP/SREBP-associated processes and reduce expression of genes involved in fatty acid and cholesterol synthesis.

3.2 Lycorine and SREBP Maturation

Lycorine can be used to investigate SCAP protein stability and the regulation of SREBP maturation. Its activity should be evaluated by separately measuring SREBP precursor proteins and mature nuclear fragments, together with downstream molecules such as fatty acid synthase, acetyl-CoA carboxylase, and HMG-CoA reductase. Reduced cellular lipid droplets alone are insufficient to demonstrate inhibition of lipogenesis.

3.3 Corylin and HSP90β

Corylin can promote degradation of mature SREBP through HSP90β-associated proteostatic regulation, thereby suppressing lipid synthesis. Because HSP90β has numerous client proteins, experiments should simultaneously assess HSP90β binding, SREBP stability, expression of lipogenic genes, and nonspecific cytotoxicity to confirm the metabolic mechanism.

3.4 Artepillin C and CREB

cAMP response element-binding protein (CREB) participates in transcription of genes associated with hepatic gluconeogenesis and lipogenesis. Artepillin C can regulate CREB and its coactivator-associated transcriptional processes, thereby suppressing gluconeogenesis and lipogenesis. This mechanism can be evaluated by measuring PEPCK, G6Pase, FASN, SREBP1, and related molecules.

4 Natural Products That Promote Lipid Breakdown and Energy Metabolism

4.1 Baicalin and CPT1A

Carnitine palmitoyltransferase 1A (CPT1A) controls the entry of long-chain fatty acids into mitochondria and is an important rate-limiting enzyme in hepatic fatty acid β-oxidation. Baicalin can regulate CPT1A-associated function, promote fatty acid oxidation, and reduce lipid deposition. Studies should jointly measure CPT1A activity, fatty acid oxidation flux, mitochondrial respiration, and intracellular triglyceride levels.

4.2 Hyperforin and the DLAT-AMPK Axis

Hyperforin can activate the AMPK-PGC-1α-UCP1 axis through a dihydrolipoamide S-acetyltransferase (DLAT)-dependent process, thereby promoting mitochondrial biogenesis, fatty acid utilization, and thermogenesis. This mechanism is suitable for evaluation in adipocyte and thermogenic-tissue models and should be validated using oxygen-consumption rate, UCP1 expression, fatty acid oxidation, and whole-body energy expenditure.

4.3 Nuciferine and Autophagy-Lysosomal Metabolism

Nuciferine can regulate HBXIP, TFEB, and autophagy-lysosomal metabolic processes, thereby affecting lipid-droplet degradation and cellular energy homeostasis. Because Nuciferine can also act on multiple neurotransmitter receptors, its lipid-lowering effects should be interpreted together with HBXIP or TFEB intervention, autophagic flux, lipid-droplet changes, and cytotoxicity results.

4.4 Puerarin and the Brain-Gut Axis

Puerarin can be used to investigate interactions among central nervous system signaling, intestinal lipid absorption, and fecal lipid excretion. Studies of the GABRA1-associated brain-gut axis can evaluate feeding behavior, intestinal motility, fecal triglyceride and fatty acid content, body weight, and adipose-tissue changes, thereby distinguishing among appetite regulation, reduced lipid absorption, and increased energy expenditure.

5 Natural Products That Block Metabolic Inflammation

5.1 Bruceine A and Galectin-1

Galectin-1 participates in cell adhesion, immune regulation, and inflammatory signaling. Bruceine A can affect NF-κB and MAPK signaling through Galectin-1-associated activity, thereby reducing metabolic inflammation. Relevant studies may assess Galectin-1 binding, phosphorylation of inflammatory pathways, and proinflammatory cytokine expression and should include Galectin-1 knockdown or competitive-inhibition controls.

5.2 Multitarget Effects of Celastrol

Celastrol can act on multiple targets, including adenylyl cyclase-associated protein 1, Nur77, and glucose-regulated protein 78, thereby influencing resistin signaling, nuclear receptor regulation, mitochondrial homeostasis, and endoplasmic reticulum stress. Its anti-inflammatory metabolic effects may involve several processes, requiring hierarchical target validation to distinguish direct binding effects from secondary anti-inflammatory responses.

Oridonin can regulate NLRP3 inflammasome-associated processes and reduce caspase-1 activation and the maturation and release of IL-1β and IL-18. Studies should simultaneously assess NLRP3-complex assembly, ASC specks, caspase-1 cleavage, and cytokine release. Reduced transcription of inflammatory cytokines alone is insufficient to demonstrate direct inhibition of the inflammasome.

5.4 HSP90-Associated Natural Products

Carnosol and Echinatin can reduce the stability and activation of NLRP3-associated protein complexes by affecting HSP90 molecular-chaperone function. Because HSP90 has a broad range of client proteins, studies should also evaluate effects on other kinases, transcription factors, mitochondrial function, and cell survival.

5.5 Licochalcone B and NEK7

NEK7 is an important regulator of NLRP3 inflammasome assembly. Licochalcone B can interfere with NEK7-NLRP3-associated interactions and inhibit inflammasome assembly and proinflammatory cytokine maturation. Its mechanism can be evaluated using protein-interaction assays, ASC-speck formation, caspase-1 activity, and IL-1β release.

5.6 Schisandrin B and MyD88

Myeloid differentiation primary response 88 (MyD88) is an adaptor protein downstream of multiple Toll-like receptors and IL-1 receptors and can activate NF-κB and MAPK signaling. By regulating MyD88-associated processes, Schisandrin B can reduce inflammatory responses induced by lipotoxicity or metabolic danger signals.

6 Natural Products That Regulate Oxidative Stress and Biological Rhythms

6.1 Ginsenoside Rb1 and Keap1-Nrf2

Ginsenoside Rb1 can regulate the Keap1-Nrf2 antioxidant pathway. After activation, Nrf2 promotes expression of heme oxygenase 1, NAD(P)H quinone oxidoreductase 1, and genes involved in glutathione synthesis, thereby increasing cellular antioxidant capacity. Ginsenoside Rb1 can also influence activity associated with the NADPH oxidase 2 subunit p47phox, regulating oxidative stress at the levels of both reactive oxygen species generation and antioxidant defense.

6.2 Nobiletin and ROR Nuclear Receptors

Nobiletin can regulate circadian rhythm-associated ROR nuclear receptors. Circadian systems participate in hepatic glucose output, fatty acid oxidation, lipid synthesis, and energy expenditure, whereas circadian disruption promotes obesity, insulin resistance, and fatty liver. Nobiletin is suitable for investigating the relationships among clock genes, nutritional status, and glucose and lipid metabolism.

6.3 Boundaries for Interpreting Antioxidant Effects

A natural product that reduces reactive oxygen species or increases SOD, CAT, and GSH levels cannot be considered to improve metabolic disorders on this basis alone. Antioxidant findings should be evaluated together with insulin signaling, lipid deposition, glucose tolerance, and tissue-function changes. The physiological role of moderate reactive oxygen species in cellular signaling and metabolic adaptation should also be considered.

7 Experimental Evaluation of Natural Products Against Metabolic Disorders

7.1 Insulin-Resistance Models

High-concentration insulin, palmitic acid, high glucose, and inflammatory cytokines can be used to establish different insulin-resistance models. High-insulin models primarily represent receptor-signaling desensitization, palmitic acid models emphasize diacylglycerol accumulation, lipotoxicity, and inflammation, whereas high-glucose models focus more strongly on glucotoxicity and oxidative stress. Candidate natural products should be validated in models that correspond to the proposed target mechanism.

7.2 Evaluation of Lipid Deposition and Fatty Acid Oxidation

Lipid accumulation in hepatocytes and adipocytes can be evaluated using triglyceride quantification, Oil Red O staining, or neutral-lipid fluorescent staining. Fatty acid oxidation should be assessed through CPT1A activity, acylcarnitine profiles, ketone bodies, oxygen-consumption rate, and metabolic-flux measurements. Reduced lipid droplets may result from decreased lipid synthesis, enhanced fatty acid oxidation, increased lipid export, or cytotoxicity and therefore requires mechanistic distinction.

7.3 Evaluation of Metabolic Inflammation

Free fatty acids, oxidized LDL, cholesterol crystals, and high glucose can be used to induce metabolic inflammation. Studies should assess NF-κB, MAPK, NLRP3, caspase-1, and inflammatory cytokines and use target knockdown, knockout, or selective inhibitors to confirm pathway dependence.

7.4 Evaluation of Oxidative Stress and Mitochondrial Function

Oxidative stress can be evaluated by measuring total reactive oxygen species, mitochondrial superoxide, lipid-peroxidation products, and antioxidant-enzyme activity. Mitochondrial function should additionally be assessed using membrane potential, ATP production, oxygen-consumption rate, and respiratory-chain function. The intrinsic color, fluorescence, and radical-scavenging activity of natural products may interfere with probe-based assays, so cell-free blanks and orthogonal methods should be included.

7.5 Direct-Target Validation

Chemical proteomics, affinity enrichment, cellular thermal shift assays, surface plasmon resonance, isothermal titration calorimetry, and enzymatic assays can be used to verify direct binding between natural products and candidate targets. Molecular docking can only propose potential binding modes and cannot replace biophysical binding assays, target-mutagenesis studies, or genetic validation.

8 Natural Products and Research Products Related to Metabolic Disorders

Natural products can regulate metabolic homeostasis through multiple processes, including insulin signaling, glucose and lipid synthesis, fatty acid oxidation, metabolic inflammation, oxidative stress, and the brain-gut axis. Their activity should be evaluated primarily on the basis of direct molecular targets, effective exposure, and improvement of metabolic function rather than solely on anti-inflammatory activity, antioxidant effects, or reductions in lipid droplets.

References

[1] Halliwell B. Understanding Mechanisms of Antioxidant Action in Health and Disease. Nat Rev Mol Cell Biol. 2024;25(1):13-33.

[2] Zheng ZG, et al. Discovery of a Potent Allosteric Activator of DGKQ That Ameliorates Obesity-Induced Insulin Resistance via the sn-1,2-DAG-PKCε Signaling Axis. Cell Metab. 2023;35(1):101-117.

[3] Chen S, et al. The Phytochemical Hyperforin Triggers Thermogenesis in Adipose Tissue via a DLAT-AMPK Signaling Axis to Curb Obesity. Cell Metab. 2021;33(3):565-580.e7.

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