• Natural Product Sciences
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• 제19권1호
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• pp.1-7
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• 2013

AMP-activated protein kinase (AMPK) is a major cellular energy sensor and master regulator of metabolic homeostasis. On activation, this cellular fuel sensing enzyme induces a series of metabolic changes to balance energy consumption via multiple downstream signaling pathways controlling nutrient uptake and energy metabolism. This pivotal role of AMPK has led to the development of numerous AMPK activators which might be used as novel drug candidates in the treatment of AMPK related disorders, diabetes, obesity, and other metabolic diseases. Consequently, a number of patents have been published on AMPK activators from natural products and other sources. This review covers the patented AMPK activators from natural products and their therapeutic potential in treatment or prevention of metabolic diseases including diabetes and obesity.

• KSBB Journal
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• 제27권1호
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• pp.57-60
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• 2012

In this study, we evaluated the effects of Biochanin A on glucose uptake in C2C12 myotube. We found that Biochanin A significantly stimulated 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose (2-NBDG) uptake in a dose-dependent manner. In addition, AMPK and PPAR-gamma activities were markedly increased by Biochanin A in a dose-dependent manner. However, Akt, an insulin dependent signaling molecule, did not change by Biochanin A. These results suggest that Biochanin A stimulates glucose uptake via AMPK and PPAR-gamma pathways.

• The Korean Journal of Physiology and Pharmacology
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• 제10권2호
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• pp.101-108
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• 2006

The aim of the present study was to elucidate whether gallic acid could modulate the inflammatory allergic reaction and to study its mechanism of action Gallic acid inhibited compound 48/80- or immunoglobulin E (IgE)-induced histamine release from mast cells. The inhibitory effect of gallic acid on the histamine release was mediated by modulation of cAMP and intracellular calcium. Gallic acid decreased the phorbol 12-myristate 13-acetate plus calcium ionophore A23187-stimulated pro-inflammatory cytokine gene expression and production such as TNF- ${\alpha}$ and IL-6 in human mast cells, and the inhibitory effect of gallic acid was on dependent nuclear factor- ${\kappa}$B and p38 mitogen-activated protein kinase. Our findings provide evidence that gallic acid inhibits mast cell-derived inflammatory allergic reaction by blocking histamine release and pro-inflammatory cytokine expression.

• Asian-Australasian Journal of Animal Sciences
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• 제32권9호
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• pp.1458-1468
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• 2019

Objective: As one of the most important metabolic organs, the liver plays vital roles in modulating the lipid metabolism. This study was to compare miRNA expression profiles of the Large White liver between two different developmental periods and to identify candidate miRNAs for lipid metabolism. Methods: Eight liver samples were collected from White Large of 70-day fetus (P70) and of 70-day piglets (D70) (with 4 biological repeats at each development period) to construct sRNA libraries. Then the eight prepared sRNA libraries were sequenced using Illumina next-generation sequencing technology on HiSeq 2500 platform. Results: As a result, we obtained 346 known and 187 novel miRNAs. Compared with the D70, 55 down- and 61 up-regulated miRNAs were shown to be significantly differentially expressed (DE). Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analysis indicated that these DE miRNAs were mainly involved in growth, development and diverse metabolic processes. They were predicted to regulate lipid metabolism through adipocytokine signaling pathway, mitogen-activated protein kinase, AMP-activated protein kinase, cyclic adenosine monophosphate, phosphatidylinositol 3 kinase/protein kinase B, and Notch signaling pathway. The four most abundantly expressed miRNAs were miR-122, miR-26a and miR-30a-5p (miR-122 only in P70), which play important roles in lipid metabolism. Integration analysis (details of mRNAs sequencing data were shown in another unpublished paper) revealed that many target genes of the DE miRNAs (miR-181b, miR-145-5p, miR-199a-5p, and miR-98) might be critical regulators in lipid metabolic process, including acyl-CoA synthetase long chain family member 4, ATP-binding casette A4, and stearyl-CoA desaturase. Thus, these miRNAs were the promising candidates for lipid metabolism. Conclusion: Our study provides the main differences in the Large White at miRNA level between two different developmental stages. It supplies a valuable database for the further function and mechanism elucidation of miRNAs in porcine liver development and lipid metabolism.

• 운동영양학회지
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• 제24권3호
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• pp.13-18
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• 2020

[Purpose] In vivo studies have demonstrated the ergogenic benefits of eleutherococcus senticosus (ES) supplementation. ES has been observed to enhance endurance capacity, improve cardiovascular function, and alter metabolic functions (e.g., increased fat utilization); however, the exact mechanisms involved remain unknown. We aimed to determine whether ES could effectively induce fat loss and improve muscle metabolic profiles through increases in lipolysis- and lipid metabolism-associated protein expression in 3T3-L1 adipocytes and C2C12 skeletal muscle cells, respectively, to uncover the direct effects of ES on adipocytes and skeletal muscle cells. [Methods] Different doses of ES extracts (0.2, 0.5, and 1.0 mg/mL) were added to cells (0.2 ES, 0.5 ES, and 1.0 ES, respectively) for 72 h and compared to the vehicle control (control). [Results] The intracellular triacylglycerol (TG) content significantly decreased (p < 0.05 for 0.2 ES, p < 0.01 for 0.5 ES and 1.0 ES) in 3T3-L1 cells. Adipose triglyceride lipase, which is involved in active lipolysis, was significantly higher in the 1.0 ES group than in the control group (p < 0.01) of 3T3-L1 adipocytes. In C2C12 cells, the mitochondrial protein voltage-dependent anion channel (VDAC) was significantly increased in the 1.0 ES group (p < 0.01). Furthermore, we found that 1.0 ES activated both 5' AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in skeletal muscle cells (p < 0.01). [Conclusion] These findings suggest that ES extracts decreased TG content, presumably by increasing lipase in adipocytes and metabolism-associated protein expression as well as mitochondrial biogenesis in muscle cells. These effects may corroborate previous in vivo findings regarding the ergogenic effects of ES supplementation.

• Journal of Veterinary Science
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• 제22권6호
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• pp.92.1-92.12
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• 2021

Background: Naringin and its aglycone naringenin are citrus-derived flavonoids with several pharmacological effects. On the other hand, the mechanism for the anti-diabetic effects of naringenin and naringin are controversial and remain to be clarified further. Objective: This study examined the relationship between glucose uptake and AMP-activated protein kinase (AMPK) phosphorylation by naringenin and naringin in high glucose-treated HepG2 cells. Methods: Glucose uptake was measured using the 2-NBDG fluorescent D-glucose analog. The phosphorylation levels of AMPK and GSK3β (Glycogen synthase kinase 3 beta) were observed by Western blotting. Molecular docking analysis was performed to evaluate the binding affinity of naringenin and naringin to the γ-subunit of AMPK. Results: The treatment with naringenin and naringin stimulated glucose uptake regardless of insulin stimulation in high glucose-treated HepG2 cells. Both flavonoids increased glucose uptake by promoting the phosphorylation of AMPK at Thr172 and increased the phosphorylation of GSK3β. Molecular docking analysis showed that both naringenin and naringin bind to the γ-subunit of AMPK with high binding affinities. In particular, naringin showed higher binding affinity than the true modulator, AMP with all three CBS domains (CBS1, 3, and 4) in the γ-subunit of AMPK. Therefore, both naringenin and naringin could be positive modulators of AMPK activation, which enhance glucose uptake regardless of insulin stimulation in high glucose-treated HepG2 cells. Conclusions: The increased phosphorylation of AMPK at Thr172 by naringenin and naringin might enhance glucose uptake regardless of insulin stimulation in high glucose treated HepG2 cells.

• 대한의생명과학회지
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• 제17권4호
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• pp.283-289
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• 2011

Our previous study demonstrated that the Korean traditional medicine Gyeongshingangjeehwan (GGEx) activates AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor ${\alpha}$ ($PPAR{\alpha}$) critical for fatty acid oxidation in skeletal muscle and C2C12 skeletal muscle cells. Thus, we examined whether GGEx can reduce lipid accumulation in these cells and tissues. After obese and type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats were treated with GGEx, we studied the effects of GGEx on skeletal muscle lipid accumulation. The effects of GGEx and/or the AMPK inhibitor compound C on lipid accumulation and expression of AMPK and $PPAR{\alpha}$ were measured in C2C12 skeletal muscle cells. Compared with lean Long-Evans Tokushima Otsuka rats, obese OLETF rats had increased triglyceride droplets. However, administration of GGEx to OLETF rats for 8 weeks significantly decreased triglyceride droplets in skeletal muscle. Consistent with the $in$ $vivo$ data, GGEx inhibited lipid accumulation, the degree of which was comparable to Wy14,643, the potent activator of $PPAR{\alpha}$. GGEx also increased skeletal muscle mRNA levels of AMPK${\alpha}1$, AMPK${\alpha}2$, and $PPAR{\alpha}$. However, compound C inhibited these effects in C2C12 cells. These results suggest that GGEx suppresses skeletal muscle lipid accumulation and this process may be mediated by AMPK and $PPAR{\alpha}$ activation.

• 한국식품영양학회지
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• 제30권5호
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• pp.1035-1041
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• 2017

(-)-Epigallocatechin-3-gallate (EGCG) is a major catechin found in green tea. It is reported that EGCG possesses various health benefits including anti-cancer, antioxidant, anti-diabetes, and anti-obesity. The objective of this study was to investigate the effects of EGCG on adipogenesis via activation of AMP-activated protein kinase (AMPK) pathway in 3T3-L1 preadipocytes. In order to determine the effects of EGCG on adipogenesis, preadipocyte differentiation was induced in the presence or absence of EGCG ($0{\sim}100{\mu}M$) for a period of 6 days. EGCG significantly inhibited fat accumulation and suppressed the expression of adipogenic specific proteins including peroxisome proliferator-activated receptor (PPAR)-${\gamma}$. Also, EGCG markedly increased the activation of AMPK and acetyl-CoA carboxylase (ACC) and the production of intracellular reactive oxygen species (ROS). However, any pretreatment with a specific AMPK inhibitor, compound C, abolished the inhibitory effects of the EGCG on $PPAR{\gamma}$ expression. This study suggests that EGCG has anti-adipogenic effects through modulation of the AMPK signaling pathway and therefore, may be a promising antiobesity agent.

• Toxicological Research
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• 제34권1호
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• pp.13-21
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• 2018

Anthocyanins are naturally occurring water-soluble polyphenolic pigments in plants that have been shown to protect against cardiovascular diseases, and certain cancers, as well as other chronic human disorders. However, the anti-obesity effects of anthocyanins are not fully understood. In this study, we investigated the effects of anthocyanins isolated from the fruit of Vitis coignetiae Pulliat on the adipogenesis of 3T3-L1 preadipocytes. Our data indicated that anthocyanins attenuated the terminal differentiation of 3T3-L1 preadipocytes, as confirmed by a decrease in the number of lipid droplets, lipid content, and triglyceride production. During this process, anthocyanins effectively enhanced the activation of the AMP-activated protein kinase (AMPK); however, this phenomenon was inhibited by the co-treatment of compound C, an inhibitor of AMPK. Anthocyanins also inhibited the expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor-${\gamma}$, CCAAT/enhancer-binding protein a and b, and sterol regulatory element-binding protein-1c. In addition, anthocyanins were found to potently inhibit the expression of adipocyte-specific genes, including adipocyte fatty acid-binding protein, leptin, and fatty acid synthase. These results indicate that anthocyanins have potent anti-obesity effects due to the inhibition of adipocyte differentiation and adipogenesis, and thus may have applications as a potential source for an anti-obesity functional food agent.

• The Korean Journal of Physiology and Pharmacology
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• 제13권6호
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• pp.449-454
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• 2009

5'-AMP-activated protein kinase (AMPK) is a heterotrimeric complex consisting of a catalytic ($\alpha$) and two regulatory ($\beta$ and $\gamma$) subunits. Two isoforms are known for catalytic subunit (${\alpha}1$, ${\alpha}2$) and are encoded by different genes. To assess the metabolic effects of $AMPK{\alpha}1$, we examined the effects of overexpression of adenoviral-mediated $AMPK{\alpha}1$ in hyperlipidemic type 2 diabetic rats. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an established animal model of type 2 diabetes that exhibits chronic and slowly progressive hyperglycemia and hyperlipidemia. Thirty five-week-old overt type 2 diabetic rats (n=10) were administered intravenously with Ad.$AMPK{\alpha}1$. AMPK activity was measured by phosphorylation of acetyl CoA carboxlyase (ACC). To investigate the changes of gene expression related glucose and lipid metabolism, quantitative real-time PCR was performed with liver tissues. Overexpression of $AMPK{\alpha}1$ showed that blood glucose concentration was decreased but that glucose tolerance was not completely recovered on 7th day after treatment. Plasma triglyceride concentration was decreased slightly, and hepatic triglyceride content was markedly reduced by decreasing expression of hepatic lipogenic genes. Overexpression of $AMPK{\alpha}1$ markedly improved hepatic steatosis and it may have effective role for improving hepatic lipid metabolism in hyperlipidemic state.