Table 1.
Summary of natural products reported in recent years and the mechanisms of their active ingredients that promote non-shivering thermogenesis via signalling pathways129.
| Signalling pathways | Source | Dietary component |
Mechanism of action | Models | Ref |
|---|---|---|---|---|---|
| cAMP-PKA | Korean ginseng | Ginsenosides (GEF) | inhibit fat accumulation and increases energy expenditure in white adipocytes through PKA activation | Mouse 3T3-L1 pre-adipocytes, Mouse primary subcutaneous adipocytes (SAT) | 130 |
| cAMP-PKA | Bitter melon seed oil (BMSO) | Cis-9, trans-11, trans-13 isomer of conjugated linolenic acid | activate PKA and program cell death in WAT | Male C57BL/6JN mice (7 weeks old) | 131 |
| cAMP-PKA | Black mustard seeds, wine, and vinegar | Sinapic acid (SA) | stimulate mitochondrial biogenesis, WAT browning and lipolysis via the p38 MAPK-CREB pathway; activate thermogenesis via PKA-CREB signalling | 3T3-L1 pre-adipocytes; BAT cells | 132, 133 |
| cAMP-PKA, AMPK | Turmeric | Curcumin | induce browning via an AMPK-mediated pathway; lead to lipid metabolism and energy homeostasis by increasing cAMP-PKA/CREB signalling pathways; promote adipogenic differentiation of preadipocytes and mitochondrial oxygen consumption | 3T3-L1 preadipocytes, Male C57BL/6 J mice (6 weeks old), Primary adipocytes, Mouse brown adipocytes, Male db/db C57BL/6 mice | 134-136, 137 |
| PKA-p38MAPK-CREB, AMPK | Mangifera indica | Mangiferin (MF) | promote thermogenesis in brown preadipocytes via activation of AMPK and PKA-p38 MAPK-CREB Signalling pathways | C3H10T1/2 MSCs, Brown preadipocytes | 138, 139 |
| cAMP-PKA, AMPK | Fruits of hazel trees | Filbertone (C8H14O) | induce cAMP and then activate PKA, thus inducing phosphorylation of AMPK and CREB and thereby inhibiting adipogenesis, resulting in increased thermogenesis | Male C57BL/6N mice (5 weeks old), 3T3-L1 pre-adipocytes | 140 |
| PKA-p38 MAPK | Cinnamon | Cinnamaldehyde (CA) | activate PKA Signalling, increase expression of thermogenic genes and induce phosphorylation of HSL and PLIN1 | Primary preadipocytes; Human adipose-derived stem cells (hASCs) | 126 |
| β3-AR-MAPK, AMPK | Many plants | Quercetin | promote UCP1 expression through the β3-AR and AMPK pathways | Male C57BL/6 mice (4 weeks old), Primary brown preadipocytes | 141 |
| PI3K-Akt | Ishige okamurae | Ishige okamurae extract (IOE) | activate the PI3K/Akt pathway and increase the expression of pro-thermogenic genes | Male db/db and lean db/+ mice (5 weeks old) | 142 |
| β3-AR-PKA, AMPK | various plants of more than 20 species, including fennel, anise, and star anise, and has been used for culinary purposes for centuries | Trans-anethole (trans-1-methyoxy-4-propenyl-benzene) | induce browning through activation of the β3-AR and AMPK-SIRT1 pathways | 3T3-L1 preadipocytes, Male C57BL/6 mice (5 weeks old) | 143 |
| PKA, AMPK | Magnolia officinalis (magnolia bark) | Magnolol | prevent oxidative stress and promote WAT browning by activating PPARγ-, pAMPK-, and PKA-mediated pathways | 3T3-L1 preadipocytes | 144 |
| PKA, AMPK | Numerous aromatic plants such as thyme species | Thymol (5-methyl-2-isopropylphenol) | induce WAT browning by activating β3-AR-PKA-p38MAPK; alleviate lipogenesis by activating the AMPK pathway | 3T3-L1 preadipocytes | 145 |
| AMPK, PI3K/AKT | Paeonia lactiflora | Albiflorin (AF) | induce brown adipogenesis by activating the AMPK and PI3K/AKT Signalling pathway | human adipose tissue-derived mesenchymal stem cells (HAMSCs), Male C57BL/6J mice (4 weeks old), Brown preadipocytes | 146 |
| PKA, AMPK-p38 MAPK | Various plants, such as dill, vanilla, violet flowers, and black pepper | Piperonal (C8H6O3) | increase PKA Signalling in WAT, regulate glucose uptake by inducing the lactate-AMPK-p38 MAPK pathway; cause mitochondrial respiration regulation via UCP1 induction | C57BL/6N mice, mouse embryo 3T3-L1 fibroblast cells, mouse C2C12 myoblasts, rat L6 myoblasts, 3T3-L1 preadipocytes | 147, 148 |
| AMPK | Panax notoginseng saponins (PNS) | Ginsenosides Rb1, Rd, Re, Rf and Rg1 and notoginsenoside R1 | increase BAT thermogenesis and beige adipocyte reconstruction by activating the leptin-AMPK/STAT3 Signalling pathway | Male C57BL/6J mice (4 weeks old), db/db and ob/ob mice | 149 |
| AMPK | Flaxseed | Secoisolariciresinol diglucoside (SDG) | increase AMPK activation pathway and thus activate thermogenesis and stimulate mitochondrial biogenesis/activation/fission | Male db/db mice (5 weeks old), Male C57BL/6J mice (4 weeks old), Brown adipocytes, Beige adipocytes, 3T3-L1 adipocytes, | 150 |
| AMPK | Citrus aurantiumLinné (CA) | - | induce adipogenesis and thermogenesis through AMPK activation | Male C57BL/6J mice (4 weeks old), 3T3-L1 preadipocytes, Brown adipocytes | 151 |
| AMPK, NF-кB, MAPK | Fruits and vegetables | Apigenin (AP) | enhance thermogenesis and browning via AMPK activation; reduce adipose tissue metabolic inflammation (NF-кB, MAPK) | Male C57BL/6 mice (3 weeks old) | 152 |
| AMPK-PGC1ɑ | Ginger rhizomes (Zingiber officinale Rosco) | Ginger extract (GE) | stimulate browning via the SIRT1/AMPK/PGC-1α pathway | Male C57BL/6 J mice (5 weeks old) | 153 |
| AMPK | Rhizoma Coptidis | Berberine (BBR) | promote brown adipocyte differentiation and BAT thermogenesis through the AMPK-PRDM16 axis; stimulate UCP1 transcription through AMPK activation | Male C57BL/6J mice (6 weeks old), Adipose-specific AMPKα1/α2 KO mice (AKO), Male db/db mice, Brown preadipocytes, Primary stromal vascular (SVF) cells, C3H10T1/2 cells | 154, 155 |
| AMPK-PGC1ɑ | Soy | Genistein | increase UCP1 expression and that of some biomarkers of browning via AMPK pathway activation | Male C57BL/6 mice (8 weeks old), 3T3-L1 preadipocytes | 156 |
| AMPK | Humulus japonicus | Aqueous extract of Humulus japonicus (AH) | stimulate browning and β-oxidation and attenuate hydrogen peroxide-induced oxidative stress via AMPK and PPARδ-mediated pathways | 3T3-L1 preadipocytes | 157 |
| AMPK | Outer bark of a variety of tree species | Betulinic acid (BA) | facilitate energy expenditure, lipid oxidation and thermogenesis by activating the AMPK pathway | 3T3-L1 mouse embryo fibroblasts, Brown adipocytes, Male C57BL/6 mice (6 weeks old) | 158 |
| AMPK | Fungus | Cordycepin (Cpn) | activate UCP1 expression through AMPK activation | Male C57BL/6 mice, 3T3-L1 preadipocytes | 159 |
| AMPK | Platycodi Radix (root of Platycodon grandiflorum) | Platycodin D (PD) | decrease adipogenic markers including PPARγ and CEBPα via AMPK pathway activation and increase thermogenic factors such as UCP1 and PGC1α | Male db/db mice and age-matched WT mice (5 weeks old), 3T3-L1 mouse embryo fibroblasts, Brown adipocytes, hAMSCs | 160 |
| AMPK | Humulus lupus | Xanthohumol (XN) | activate AMPK resulting in beiging of 3T3-L1 adipocytes, enhance lipolysis and inhibit adipogenesis | 3T3-L1 mouse embryo preadipocyte cell, Primary human subcutaneous preadipocytes | 161 |
| AMPK | Raspberry (RAS) | polyphenols | stimulate the expression of thermogenic genes and beige adipocyte formation through the AMPK pathway | Male RosaCre/AMPKα1flox/floxC57BL/6 mice, and age‐matched WT mice (2 months old) | 162 |
| AMPK | Angelica sinensis | Vanillic acid (VA) | inhibit adipogenic factors through the AMPK pathway and decrease lipid accumulation by suppressing adipogenic factors | Male C57BL/6J mice (4 weeks old), Male db/db mice and age‐matched WT heterozygous mice(5 weeks old), Brown preadipocytes, HepG2 cells, 3T3‐L1 cells, Primary brown adipocytes | 163 |
| AMPK | Many essential oils | Farnesol | induce mitochondrial/peroxisomal biogenesis and thermogenesis by enhancing the AMPK Signalling pathway in BAT | Male C57BL/6 J mice (4/7 weeks old), Brown preadipocytes | 164 |
| AMPK | Many types of plants, microalgae, and some bacteria | Gallic acid [3,4,5-trihydroxybenzoic acid (GA)] | elevate thermogenic gene expressions and activate the AMPK/Sirt1/PGC1α pathway in interscapular brown adipose tissue | HepG2 cells, Male C57BL/6 mice (10-12 weeks old) | 165 |
| AMPK | Rhubarb | Chrysophanic Acid | activate the AMPK pathway and then suppress adipogenesis and induce thermogenesis | Male C57BL/6J mice (4 weeks old), 3T3-L1 preadipocytes, Brown adipocytes | 166 |
| NF-κB, TLR-4, AMPK | Green tea | (-)-Epigallocatechin-3-gallate (EGCG) | raise mitochondrial biogenesis in BAT; inhibit the NF-κB and STAT3 pathways; increase the expression of TLR-4 by suppressing the expression of Elf-1; increase mtDNA replication and AMPK activation in BAT | Male C57BL/6J mice (4 weeks old), Male BALB/c mice (8 weeks old), Peritoneal macrophages | 167-169 |
| AMPK | Many edible and medicinal plants such as pepper, celery, thyme, peppermint and honeysuckle | Luteolin | elevate thermogenic gene expressions and activate AMPK/PGC1α signalling in differentiated primary brown and subcutaneous adipocytes | Male C57BL/6 mice (4 weeks old), Primary brown adipocytes, Subcutaneous adipocytes | 170 |
| TRPA1, TRPV1 | Durian | Sulphur-containing compounds (DEDS, DPDS, DETS DPTS, and PT) | induce Ca2+ responses in TRPA1- or TRPV1-expressing cells and then activate both TRPA1 and TRPV1 | Human TRPA1- or TRPV1-expressing HEK cells | 125 |
| TRP | Royal Jelly (RJ) | 10-hydroxy-Trans- 2-decenoic acid (HDEA) and Hydroxydecanoic acid (HDAA) | enhance thermogenic gene expressions; activate the TRP channels, specially TRPA1 in sensory neurons of the gastrointestinal tract; promote thermogenesis via β-AR-mediated pathway in brown and white adipocytes (TRP-SNS-UCP1 axis) | Male Wistar rats (3 weeks old) | 123, 124 |