Ageing Abstracts 4

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Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome.
            (Cool et al., 2006) Download
AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular and whole-body energy metabolism. We have identified a thienopyridone family of AMPK activators. A-769662 directly stimulated partially purified rat liver AMPK (EC50 = 0.8 microM) and inhibited fatty acid synthesis in primary rat hepatocytes (IC50 = 3.2 microM). Short-term treatment of normal Sprague Dawley rats with A-769662 decreased liver malonyl CoA levels and the respiratory exchange ratio, VCO2/VO2, indicating an increased rate of whole-body fatty acid oxidation. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreased hepatic expression of PEPCK, G6Pase, and FAS, lowered plasma glucose by 40%, reduced body weight gain and significantly decreased both plasma and liver triglyceride levels. These results demonstrate that small molecule-mediated activation of AMPK in vivo is feasible and represents a promising approach for the treatment of type 2 diabetes and the metabolic syndrome.

Heat-processed Gynostemma pentaphyllum extract improves obesity in ob/ob mice by activating AMP-activated protein kinase.
            (Gauhar et al., 2012) Download
Gynostemma pentaphyllum is widely used in Asian countries as a herbal medicine to treat dyslipidemia, type 2 diabetes and inflammation. An ethanol extract of G. pentaphyllum lessened obesity by activating AMP-activated protein kinase (AMPK). The levels of damulins A and B, components responsible for AMPK activation in the extract, were increased by autoclaving in a time-dependent manner. Heat-processed G. pentaphyllum extract, actiponin containing damulins A (0.93 %, w/w) and B (0.68 %, w/w), significantly stimulated fat oxidation and glucose uptake via AMPK activation in L6 myotube cells. Oral administration of actiponin to ob/ob mice for 8 weeks decreased body weight gain, liver weight, and blood cholesterol levels with AMPK activation in the soleus muscle. Our results demonstrate the beneficial effect of G. pentaphyllum on improving obesity and have elucidated the underlying molecular mechanisms.


Tiliroside, a glycosidic flavonoid, ameliorates obesity-induced metabolic disorders via activation of adiponectin signaling followed by enhancement of fatty acid oxidation in liver and skeletal muscle in obese-diabetic mice.
            (Goto et al., 2012) Download
Tiliroside contained in several dietary plants, such as rose hips, strawberry and raspberry, is a glycosidic flavonoid and possesses anti-inflammatory, antioxidant, anticarcinogenic and hepatoprotective activities. Recently, it has been reported that the administration of tiliroside significantly inhibited body weight gain and visceral fat accumulation in normal mice. In this study, we evaluated the effects of tiliroside on obesity-induced metabolic disorders in obese-diabetic KK-A(y) mice. In KK-A(y) mice, the administration of tiliroside (100 mg/kg body weight/day) for 21 days failed to suppress body weight gain and visceral fat accumulation. Although tiliroside did not affect oxygen consumption, respiratory exchange ratio was significantly decreased in mice treated with tiliroside. In the analysis of metabolic characteristics, it was shown that plasma insulin, free fatty acid and triglyceride levels were decreased, and plasma adiponectin levels were increased in mice administered tiliroside. The messenger RNA expression levels of hepatic adiponectin receptor (AdipoR)-1 and AdipoR2 and skeletal muscular AdipoR1 were up-regulated by tiliroside treatment. Furthermore, it was indicated that tiliroside treatment activated AMP-activated protein kinase in both the liver and skeletal muscle and peroxisome proliferator-activated receptor alpha in the liver. Finally, tiliroside inhibited obesity-induced hepatic and muscular triglyceride accumulation. These findings suggest that tiliroside enhances fatty acid oxidation via the enhancement adiponectin signaling associated with the activation of both AMP-activated protein kinase and peroxisome proliferator-activated receptor alpha and ameliorates obesity-induced metabolic disorders, such as hyperinsulinemia and hyperlipidemia, although it does not suppress body weight gain and visceral fat accumulation in obese-diabetic model mice.

AMP-activated protein kinase: a master switch in glucose and lipid metabolism.
            (Hardie, 2004) Download

AMP-activated protein kinase: a potential target for the diseases prevention by natural occurring polyphenols.
            (Hwang et al., 2009) Download
A reduced life span is an outcome associated with many prevalent diseases, including diabetes, obesity, and high blood pressure. In seeking to prevent these diseases, many researchers have looked into potential therapeutic benefits of naturally occurring compounds. AMP-activated protein kinase (AMPK) is a major metabolic-sensing protein implicated in the prevention of metabolic disorders, or in minimizing the effects thereof, via the regulation of both upstream and downstream target molecules. In the field of food and nutrition, the current focus lies in the finding of components that activate AMPK. AMPK is a serine/threonine protein kinase and is activated by several natural compounds, including resveratrol, epigallocatechin gallate, berberine, and quercetin. AMPK activation can induce ATP (adenosine triphosphate) generation through pathways such as glycolysis and beta-oxidation. By contrast, ATP-consuming pathways, including fatty acid and cholesterol syntheses, and gluconeogenesis, are suppressed by AMPK activation. In this review, we will discuss how the activation of AMPK by naturally occurring compounds could help to prevent the development of numerous diseases; the potential mechanism underlying these effects will also be addressed.

Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK.
            (Ix and Sharma, 2010) Download
Obesity is a risk factor for chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD). Recent studies identify mechanisms common to both diseases linked through an interorgan communication orchestrated by fetuin-A and adiponectin. In liver and kidney, the energy sensor 5'-AMP activated protein kinase (AMPK) is pivotal to directing podocytes and hepatocytes to compensatory and potentially deleterious pathways, leading to inflammatory and profibrotic cascades culminating in end-organ damage. Regulation of these early upstream pathways may provide new therapeutic targets for these increasingly common sequelae of obesity.

Reduction of body weight by dietary garlic is associated with an increase in uncoupling protein mRNA expression and activation of AMP-activated protein kinase in diet-induced obese mice.
            (Lee et al., 2011) Download
This study investigated the antiobesity effect of garlic in diet-induced obese mice. Male C57BL/6J mice were fed a high-fat diet (45% fat) for 8 wk to induce obesity. Subsequently, they were fed a high-fat control diet, high-fat diets supplemented with 2%, or 5% garlic (wt:wt) for another 7 wk. Dietary garlic reduced body weight and the mass of various white adipose tissue deposits and also ameliorated the high-fat diet-induced abnormal plasma and liver lipid profiles. Garlic supplementation significantly decreased the mRNA levels of adipogenic genes in white adipose tissues (WAT). However, consumption of garlic increased the expression of mRNA for uncoupling proteins in brown adipose tissue (BAT), liver, WAT, and skeletal muscle. Mice treated with garlic maintained a significantly higher body temperature than untreated mice during a 6-h, 4 degrees C cold challenge and, notably, AMP-activated protein kinase (AMPK) activity was stimulated in BAT, liver, WAT, and skeletal muscle. These results suggest that the antiobesity effects of garlic were at least partially mediated via activation of AMPK, increased thermogenesis, and decreased expression of multiple genes involved in adipogenesis.

Isolation and antitumor activities of acidic polysaccharide from Gynostemma pentaphyllum Makino.
            (Li et al., 2012) Download
Two acidic polysaccharides (GP-B1 and GP-C1) were obtained from Gynostemma pentaphyllum. The molecular weights (Mw) of the two fractions were 79 kDa for GP-B1 and 126 kDa for GP-C1. GP-B1 was composed of Gal, Ara, Man, Rha, Xyl, Glc, GalA and GlcA in a molar ration of 3.5:3.2:0.6:0.9:0.3:0.5:0.6:0.4. GP-C1 consisted of Gal, Ara, Man, Rha, Glc, and GlcA in the proportions of 2.1:1.0:0.3:0.5:0.4:0.9. Among them, GP-B1 treatment had a significant inhibitory effect on the growth of melanoma B16 in vivo and in vitro. Meanwhile GP-B1 could increase the relative spleen weight and stimulate the splenocyte proliferation alone or combined with ConA. Moreover, GP-B1 treatment induced an evident increase in the level of serum TNF-alpha, IFN-gamma, and IL-12 and a reduction for IL-10 production. These results indicate that the antitumor effects of GP-B1 are associated with immunostimulation.

AMPK as a mediator of hormonal signalling.
            (Lim et al., 2010) Download
AMP-activated protein kinase (AMPK) is a key molecular player in energy homeostasis at both cellular and whole-body levels. AMPK has been shown to mediate the metabolic effects of hormones such as leptin, ghrelin, adiponectin, glucocorticoids and insulin as well as cannabinoids. Generally, activated AMPK stimulates catabolic pathways (glycolysis, fatty acid oxidation and mitochondrial biogenesis) and inhibits anabolic pathways (gluconeogenesis, glycogen, fatty acid and protein synthesis), and has a direct appetite-regulating effect in the hypothalamus. Drugs that activate AMPK, namely metformin and thiazolidinediones, are often used to treat metabolic disorders. Thus, AMPK is now recognised as a potential target for the treatment of obesity and associated co-morbidities.


 

Sirtuins in aging and age-related disease.
            (Longo and Kennedy, 2006) Download
Sirtuins have been the focus of intense scrutiny since the discovery of Sir2 as a yeast longevity factor. Functioning as either deacetylases or ADP ribosylases, Sirtuins are regulated by the cofactor NAD and thus may serve as sensors of the metabolic state of the cell and organism. Here we examine the roles of Sirtuins in diverse eukaryotic species, with special emphasis on their links to aging and age-related diseases including cancer, diabetes, and neurodegenerative disorders.

Leptin activates hepatic 5'-AMP-activated protein kinase through sympathetic nervous system and alpha1-adrenergic receptor: a potential mechanism for improvement of fatty liver in lipodystrophy by leptin.
            (Miyamoto et al., 2012) Download
BACKGROUND: AMPK activation promotes glucose and lipid metabolism. RESULTS: Hepatic AMPK activities were decreased in fatty liver from lipodystrophic mice, and leptin activated the hepatic AMPK via the alpha-adrenergic effect. CONCLUSION: Leptin improved the fatty liver possibly by activating hepatic AMPK through the central and sympathetic nervous systems. SIGNIFICANCE: Hepatic AMPK plays significant roles in the pathophysiology of lipodystrophy and metabolic action of leptin. Leptin is an adipocyte-derived hormone that regulates energy homeostasis. Leptin treatment strikingly ameliorates metabolic disorders of lipodystrophy, which exhibits ectopic fat accumulation and severe insulin-resistant diabetes due to a paucity of adipose tissue. Although leptin is shown to activate 5'-AMP-activated protein kinase (AMPK) in the skeletal muscle, the effect of leptin in the liver is still unclear. We investigated the effect of leptin on hepatic AMPK and its pathophysiological relevance in A-ZIP/F-1 mice, a model of generalized lipodystrophy. Here, we demonstrated that leptin activates hepatic AMPK through the central nervous system and alpha-adrenergic sympathetic nerves. AMPK activities were decreased in the fatty liver of A-ZIP/F-1 mice, and leptin administration increased AMPK activities in the liver as well as in skeletal muscle with significant reduction in triglyceride content. Activation of hepatic AMPK with A769662 also led to a decrease in hepatic triglyceride content and blood glucose levels in A-ZIP/F-1 mice. These results indicate that the down-regulation of hepatic AMPK activities plays a pathophysiological role in the metabolic disturbances of lipodystrophy, and the hepatic AMPK activation is involved in the therapeutic effects of leptin.


 

Prevention of free fatty acid-induced lipid accumulation, oxidative stress, and cell death in primary hepatocyte cultures by a Gynostemma pentaphyllum extract.
            (Muller et al., 2012) Download
Hepatocytes of a primary cell culture that are exposed to high glucose, insulin, and linoleic (LA) acid concentration respond with lipid accumulation, oxidative stress up to cell death. Such alterations are typically found in patients with non-alcoholic fatty liver disease (NAFLD). We used this cellular model to study the effect of an ethanolic Gynostemma pentaphyllum (GP) extract in NAFLD. When hepatocytes were cultured in the presence of high insulin, glucose, and LA concentration the extract completely protected the cells from cell death. In parallel, the extract prevented accumulation of triglycerides (TGs) and cholesterol as well as oxidative stress. Our data further demonstrate that GP stimulates the production of nitric oxide (NO) in hepatocytes and affects the molecular composition of the mitochondrial phospholipid cardiolipin (CL). We conclude that GP is able to protect hepatocytes from cell death, lipid accumulation, and oxidative stress caused by diabetic-like metabolism and lipotoxicity. Therefore, GP could be beneficial for patients with diabetes mellitus and NAFLD.

Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK.
            (Murase et al., 2010) Download
AMP-activated protein kinase (AMPK) is a serine/threonine kinase that is implicated in the control of energy metabolism and is considered to be a molecular target for the suppression of obesity and the treatment of metabolic syndrome. Here, we identified and characterized nootkatone, a constituent of grapefruit, as a naturally occurring AMPK activator. Nootkatone induced an increase in AMPKalpha1 and -alpha2 activity along with an increase in the AMP/ATP ratio and an increase the phosphorylation of AMPKalpha and the downstream target acetyl-CoA carboxylase (ACC), in C(2)C(12) cells. Nootkatone-induced activation of AMPK was possibly mediated both by LKB1 and Ca(2+)/calmodulin-dependent protein kinase kinase. Nootkatone also upregulated PPARgamma coactivator-1alpha in C(2)C(12) cells and C57BL/6J mouse muscle. In addition, administration of nootkatone (200 mg/kg body wt) significantly enhanced AMPK activity, accompanied by LKB1, AMPK, and ACC phosphorylation in the liver and muscle of mice. Whole body energy expenditure evaluated by indirect calorimetry was also increased by nootkatone administration. Long-term intake of diets containing 0.1% to 0.3% (wt/wt) nootkatone significantly reduced high-fat and high-sucrose diet-induced body weight gain, abdominal fat accumulation, and the development of hyperglycemia, hyperinsulinemia, and hyperleptinemia in C57BL/6J mice. Furthermore, endurance capacity, evaluated as swimming time to exhaustion in BALB/c mice, was 21% longer in mice fed 0.2% nootkatone than in control mice. These findings indicate that long-term intake of nootkatone is beneficial toward preventing obesity and improving physical performance and that these effects are due, at least in part, to enhanced energy metabolism through AMPK activation in skeletal muscle and liver.

Rosehip Extract Inhibits Lipid Accumulation in White Adipose Tissue by Suppressing the Expression of Peroxisome Proliferator-activated Receptor Gamma.
            (Nagatomo et al., 2013) Download
Recent studies have shown that Rosa canina L. and tiliroside, the principal constituent of its seeds, exhibit anti-obesity and anti-diabetic activities via enhancement of fatty acid oxidation in the liver and skeletal muscle. However, the effects of rosehip, the fruit of this plant, extract (RHE), or tiliroside on lipid accumulation in adipocytes have not been analyzed. We investigated the effects of RHE and tiliroside on lipid accumulation and protein expression of key transcription factors in both in vitro and in vivo models. RHE and tiliroside inhibited lipid accumulation in a dose-dependent manner in 3T3-L1 cells. We also analyzed the inhibitory effect of RHE on white adipose tissue (WAT) in high-fat diet (HFD)-induced obesity mice model. Male C57BL/6J mice were fed HFD or HFD supplemented with 1% RHE (HFDRH) for 8 weeks. The HFDRH-fed group gained less body weight and had less visceral fat than the HFD-fed group. Liver weight was significantly lower in the HFDRH-fed group and total hepatic lipid and triglyceride (TG) content was also reduced. A significant reduction in the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) was observed in epididymal fat in the HFDRH-fed group, in comparison with controls, through Western blotting. These results suggest that downregulation of PPARgamma expression is involved, at least in part, in the suppressive effect of RHE on lipid accumulation in WAT.

Potent anti-obese principle from Rosa canina: structural requirements and mode of action of trans-tiliroside.
            (Ninomiya et al., 2007) Download
The 80% aqueous acetone extracts from the fruit (50 mg/kg/d) and seeds (12.5 and 25 mg/kg/d) of Rosa canina L., but not from the pericarps, were found to show substantial inhibitory effect on the gain of body weight and/or weight of visceral fat without affecting food intake in mice for 2 weeks after administration of the extracts. With regard to the active constituents, the principal constituent, trans-tiliroside (0.1-10 mg/kg/d), potently inhibited the gain of body weight, especially visceral fat weight, and significantly reduced blood glucose levels after glucose loading (1 g/kg, ip) in mice. On the other hand, kaempferol and p-coumaric acid lacked such effect and kaempferol 3-O-beta-D-glucopyranoside tended to reduce the gain of body weight and visceral fat weight, but not significantly, at a dose of 10 mg/kg/d. These results indicate the importance of both kaempferol 3-O-beta-D-glucopyranoside and p-coumaroyl moieties for anti-obese effects. Furthermore, a single oral administration of trans-tiliroside at a dose of 10 mg/kg increased the expression of PPAR-alpha mRNA of liver tissue in mice.

New dammarane-type glucosides as potential activators of AMP-activated protein kinase (AMPK) from Gynostemma pentaphyllum.
            (Nguyen et al., 2011) Download
AMP-activated protein kinase (AMPK) is a key sensor and regulator of glucose, lipid, and energy metabolism throughout the body. Activation of AMPK improves metabolic abnormalities associated with metabolic diseases including obesity and type-2 diabetes. The oriental traditional medicinal herbal plant, Gynostemma pentaphyllum, has shown a wide range of beneficial effects on glucose and lipid metabolism. In this study, we found that G. pentaphyllum contains two novel dammarane-type saponins designated as damulin A (1), 2alpha,3beta,12beta-trihydroxydammar-20(22)-E,24-diene-3-O-[beta-D-glucopyranosyl -(1-->2)-beta-D-glucopyranoside], and damulin B (2), 2alpha,3beta,12beta-trihydroxydammar-20,24-diene-3-O-[beta-D-glucopyranosyl-(1--> 2)-beta-D-glucopyranoside], that strongly activate AMPK in cultured L6 myotube cells. Damulins A and B also increased beta-oxidation and glucose uptake with increasing GluT4 translocation to the plasma membrane in L6 myotube cells. Taken together our results indicate that activation of AMPK by damulins A and B may contribute to beneficial effect of G. pentaphyllum on glucose and lipid metabolism.

Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): a randomized, double-blind, placebo-controlled trial.
            (Park et al., 2014b) Download
OBJECTIVE: The effects of actiponin was investigated, a heat-processed Gynostemma pentaphyllum extract, on body weight, fat loss, and metabolic markers of Korean participants in a 12-week, randomized, double-blind, placebo-controlled clinical trial. DESIGN AND METHODS: Obese participants (BMI >/= 25 kg m(-2) and WHR >/= 0.90 for male or WHR >/= 0.85 for female) who had not been diagnosed with any disease and met the inclusion criteria were recruited for this study. The 80 subjects were randomly divided into actiponin (n = 40, 450 mg day(-1) ) and placebo (n = 40) groups. Outcomes included measurement of efficacy (abdominal fat distribution, anthropometric parameters, and blood lipid profiles) and safety (adverse events, laboratory test results, electrocardiogram data, and vital signs). RESULTS: During 12-week of actiponin supplementation, total abdominal fat area, body weight, body fat mass, percent body fat, and BMI were significantly decreased (P = 0.044, P < 0.05, P < 0.0001, P < 0.0001, and P < 0.05, respectively) in the actiponin group compared to the placebo group. No clinically significant changes in any safety parameter were observed. CONCLUSION: Our study revealed that actiponin is a potent antiobesity reagent that does not produce any significant adverse effects. These results suggest that actiponin supplementation may be effective for treating obese individuals.

Pomegranate vinegar beverage reduces visceral fat accumulation in association with AMPK activation in overweight women: A double-blind, randomized, and placebo-controlled trial
            (Park et al., 2014a) Download
Abstract Recent studies on animals have suggested that vinegar consumption may confer an antiobesity effect through the activation of the AMP-activated protein kinase (AMPK) signaling pathway. However, mechanisms of action in humans remain largely unknown. A randomized, double-blind, placebo-controlled trial was performed to examine whether a pomegranate vinegar (PV) beverage alleviates adiposity in overweight subjects, with emphasis on AMPK activation. Seventy-eight overweight women (BMI ≥ 25) were randomly assigned to receive either PV (1.5 g acetic acid and 700 μg ellagic acid/200 mL/day) or a placebo for 8 weeks. The PV reduced visceral adipose tissue, as measured by computed tomography (P = 0.037), and enhanced AMPK phosphorylation (P = 0.013) compared with the placebo group. The PV tended to suppress downstream gene expression, such as that of sterol regulatory element binding protein-1c and acetyl coenzyme carboxylase, in adipose tissue. Together, these data suggest that PV is an excellent AMPK activator and may exert beneficial effects on adiposity.

AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: impact on healthspan and lifespan.
            (Salminen et al., 2011) Download
Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of energy metabolic homeostasis and thus a major survival factor in a variety of metabolic stresses and also in the aging process. Metabolic syndrome is associated with a low-grade, chronic inflammation, primarily in adipose tissue. A low-level of inflammation is also present in the aging process. There are emerging results indicating that AMPK signaling can inhibit the inflammatory responses induced by the nuclear factor-kappaB (NF-kappaB) system. The NF-kappaB subunits are not direct phosphorylation targets of AMPK, but the inhibition of NF-kappaB signaling is mediated by several downstream targets of AMPK, e.g., SIRT1, PGC-1alpha, p53, and Forkhead box O (FoxO) factors. AMPK signaling seems to enhance energy metabolism while it can repress inflammatory responses linked to chronic stress, e.g., in nutritional overload and during the aging process. AMPK can inhibit endoplasmic reticulum and oxidative stresses which are involved in metabolic disorders and the aging process. Interestingly, many target proteins of AMPK are so-called longevity factors, e.g., SIRT1, p53, and FoxOs, which not only can increase the stress resistance and extend the lifespan of many organisms but also inhibit the inflammatory responses. The activation capacity of AMPK declines in metabolic stress and with aging which could augment the metabolic diseases and accelerate the aging process. We will review the AMPK pathways involved in the inhibition of NF-kappaB signaling and suppression of inflammation. We also emphasize that the capacity of AMPK to repress inflammatory responses can have a significant impact on both healthspan and lifespan.

Tiliroside-derivatives enhance GLUT4 translocation via AMPK in muscle cells.
            (Shi et al., 2011) Download
Tiliroside isolated from Chinese herb Potentilla chinensis showed therapeutic activities in diabetes. We synthesized 7 tiliroside-derivatives and examined their effects on surface GLUT4myc levels in muscle cells. Derivatives 2a and 3 increased surface GLUT4myc levels, and derivative 3 has the greatest potential. AMPK may be involved in tiliroside-derivatives-regulated GLUT4myc traffic.

Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies.
            (Stenesen et al., 2013) Download
A common thread among conserved life span regulators lies within intertwined roles in metabolism and energy homeostasis. We show that heterozygous mutations of AMP biosynthetic enzymes extend Drosophila life span. The life span benefit of these mutations depends upon increased AMP:ATP and ADP:ATP ratios and adenosine monophosphate-activated protein kinase (AMPK). Transgenic expression of AMPK in adult fat body or adult muscle, key metabolic tissues, extended life span, while AMPK RNAi reduced life span. Supplementing adenine, a substrate for AMP biosynthesis, to the diet of long-lived AMP biosynthesis mutants reversed life span extension. Remarkably, this simple change in diet also blocked the prolongevity effects of dietary restriction. These data establish AMP biosynthesis, adenosine nucleotide ratios, and AMPK as determinants of adult life span; provide a mechanistic link between cellular anabolism and energy sensing pathways; and indicate that dietary adenine manipulations might alter metabolism to influence animal life span.

 


References

Cool, B, et al. (2006), ‘Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome.’, Cell Metab, 3 (6), 403-16. PubMedID: 16753576
Gauhar, R, et al. (2012), ‘Heat-processed Gynostemma pentaphyllum extract improves obesity in ob/ob mice by activating AMP-activated protein kinase.’, Biotechnol Lett, 34 (9), 1607-16. PubMedID: 22576281
Goto, T, et al. (2012), ‘Tiliroside, a glycosidic flavonoid, ameliorates obesity-induced metabolic disorders via activation of adiponectin signaling followed by enhancement of fatty acid oxidation in liver and skeletal muscle in obese-diabetic mice.’, J Nutr Biochem, 23 (7), 768-76. PubMedID: 21889885
Hardie, DG (2004), ‘AMP-activated protein kinase: a master switch in glucose and lipid metabolism.’, Rev Endocr Metab Disord, 5 (2), 119-25. PubMedID: 15041787
Hwang, JT, DY Kwon, and SH Yoon (2009), ‘AMP-activated protein kinase: a potential target for the diseases prevention by natural occurring polyphenols.’, N Biotechnol, 26 (1-2), 17-22. PubMedID: 19818314
Ix, JH and K Sharma (2010), ‘Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK.’, J Am Soc Nephrol, 21 (3), 406-12. PubMedID: 20150538
Lee, MS, et al. (2011), ‘Reduction of body weight by dietary garlic is associated with an increase in uncoupling protein mRNA expression and activation of AMP-activated protein kinase in diet-induced obese mice.’, J Nutr, 141 (11), 1947-53. PubMedID: 21918057
Li, XL, et al. (2012), ‘Isolation and antitumor activities of acidic polysaccharide from Gynostemma pentaphyllum Makino.’, Carbohydr Polym, 89 (3), 942-47. PubMedID: 24750884
Lim, CT, B Kola, and M Korbonits (2010), ‘AMPK as a mediator of hormonal signalling.’, J Mol Endocrinol, 44 (2), 87-97. PubMedID: 19625456
Longo, VD and BK Kennedy (2006), ‘Sirtuins in aging and age-related disease.’, Cell, 126 (2), 257-68. PubMedID: 16873059
Miyamoto, L, et al. (2012), ‘Leptin activates hepatic 5’-AMP-activated protein kinase through sympathetic nervous system and alpha1-adrenergic receptor: a potential mechanism for improvement of fatty liver in lipodystrophy by leptin.’, J Biol Chem, 287 (48), 40441-47. PubMedID: 23024365
Muller, C, et al. (2012), ‘Prevention of free fatty acid-induced lipid accumulation, oxidative stress, and cell death in primary hepatocyte cultures by a Gynostemma pentaphyllum extract.’, Phytomedicine, 19 (5), 395-401. PubMedID: 22381945
Murase, T, et al. (2010), ‘Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK.’, Am J Physiol Endocrinol Metab, 299 (2), E266-75. PubMedID: 20501876
Nagatomo, A, et al. (2013), ‘Rosehip Extract Inhibits Lipid Accumulation in White Adipose Tissue by Suppressing the Expression of Peroxisome Proliferator-activated Receptor Gamma.’, Prev Nutr Food Sci, 18 (2), 85-91. PubMedID: 24471115
Nguyen, PH, et al. (2011), ‘New dammarane-type glucosides as potential activators of AMP-activated protein kinase (AMPK) from Gynostemma pentaphyllum.’, Bioorg Med Chem, 19 (21), 6254-60. PubMedID: 21978948
Ninomiya, K, et al. (2007), ‘Potent anti-obese principle from Rosa canina: structural requirements and mode of action of trans-tiliroside.’, Bioorg Med Chem Lett, 17 (11), 3059-64. PubMedID: 17400451
Park, Ji Eun, et al. (2014a), ‘Pomegranate vinegar beverage reduces visceral fat accumulation in association with AMPK activation in overweight women: A double-blind, randomized, and placebo-controlled trial’, Journal of Functional Foods, 8 (0), 274-81. PubMedID:
Park, SH, et al. (2014b), ‘Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): a randomized, double-blind, placebo-controlled trial.’, Obesity (Silver Spring), 22 (1), 63-71. PubMedID: 23804546
Salminen, A, JM Hyttinen, and K Kaarniranta (2011), ‘AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: impact on healthspan and lifespan.’, J Mol Med (Berl), 89 (7), 667-76. PubMedID: 21431325
Shi, L, et al. (2011), ‘Tiliroside-derivatives enhance GLUT4 translocation via AMPK in muscle cells.’, Diabetes Res Clin Pract, 92 (2), e41-46. PubMedID: 21376414
Stenesen, D, et al. (2013), ‘Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies.’, Cell Metab, 17 (1), 101-12. PubMedID: 23312286