AMP activated protein kinase: a next generation target for total metabolic control

Misra, Pankaj

doi:10.1517/14728222.12.1.91

Cited by 104 publications

(71 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the known stimulation of fatty acid oxidation by metformin in this study and others (21)(22)(23)(24) is incommensurate with mitochondrial respiratory inhibition. Add to that the current finding that direct inhibition by rotenone did not stimulate respiration at any level, and the fact that adenylate kinase knockdown prevents stimulation by depolarization but not metformin, and it becomes clear that a separate mechanism for metformin action is needed.…”

Section: Discussioncontrasting

confidence: 58%

See 1 more Smart Citation

Metformin Activates AMP Kinase through Inhibition of AMP Deaminase

Ouyang

Parakhia

Ochs

2011

Journal of Biological Chemistry

209

181

View full text Add to dashboard Cite

The mechanism for how metformin activates AMPK (AMPactivated kinase) was investigated in isolated skeletal muscle L6 cells. A widely held notion is that inhibition of the mitochondrial respiratory chain is central to the mechanism. We also considered other proposals for metformin action. As metabolic pathway markers, we focused on glucose transport and fatty acid oxidation. We also confirmed metformin actions on other metabolic processes in L6 cells. Metformin stimulated both glucose transport and fatty acid oxidation. The mitochondrial Complex I inhibitor rotenone also stimulated glucose transport but it inhibited fatty acid oxidation, independently of metformin. The peroxynitrite generator 3-morpholinosydnonimine stimulated glucose transport, but inhibited fatty acid oxidation. Addition of the nitric oxide precursor arginine to cells did not affect glucose transport. These studies differentiate metformin from inhibition of mitochondrial respiration and from active nitrogen species. Knockdown of adenylate kinase also failed to affect metformin stimulation of glucose transport. Hence, any means of increase in ADP appears not to be involved in the metformin mechanism. Knockdown of LKB1, an upstream kinase and AMPK activator, did not affect metformin action. Having ruled out existing proposals, we suggest a new one: metformin might increase AMP through inhibition of AMP deaminase (AMPD). We found that metformin inhibited purified AMP deaminase activity. Furthermore, a known inhibitor of AMPD stimulated glucose uptake and fatty acid oxidation. Both metformin and the AMPD inhibitor suppressed ammonia accumulation by the cells. Knockdown of AMPD obviated metformin stimulation of glucose transport. We conclude that AMPD inhibition is the mechanism of metformin action.

show abstract

Section: Discussioncontrasting

confidence: 58%

“…In both of these tissues, metformin stimulates fatty acid oxidation (21)(22)(23)(24). It is difficult to rationalize an inhibition of respiration with a stimulation of fatty acid oxidation.…”

mentioning

confidence: 99%

Metformin Activates AMP Kinase through Inhibition of AMP Deaminase

Ouyang

Parakhia

Ochs

2011

Journal of Biological Chemistry

209

181

View full text Add to dashboard Cite

show abstract

“…Two major classes of insulin-sensitizing drug, the biguanides and the thiazolidinediones, appear to exert their therapeutic effects by activating AMPK. This suggests that activators of AMPK may be useful for treatment of certain metabolic disorders, type 2 diabetes, and obesity [33] .…”

Section: Discussionmentioning

confidence: 99%

Long-term baicalin administration ameliorates metabolic disorders and hepatic steatosis in rats given a high-fat diet

et al. 2009

View full text Add to dashboard Cite

Aim: Baicalin, one of the major flavonoids in Scutellaria baicalensis, possesses antioxidant and anti-inflammatory properties. However, the effects of baicalin on metabolic disorders and hepatic steatosis have not been investigated. Methods: Body weight was examined in high-fat diet (HFD)-fed rats with or without baicalin treatment. At the end of the experiment, serum biochemical parameters, liver histology and lipid profile were analyzed to assess whether the animals were suffering from metabolic disorders or hepatic steatosis. In the liver, the phosphorylation of AMP activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) and the gene expression of some enzymes involved in lipogenesis were examined. The effects of baicalin on the phosphorylation of AMPK and lipid accumulation induced by high glucose in human hepatoma HepG2 cells were also examined. Results: Baicalin (80 mg/kg) administered ip for 16 weeks suppressed body weight gain in HFD-fed rats. Weight reduction was accompanied by the reduction of visceral fat mass. Baicalin significantly decreased the elevated serum cholesterol, free fatty acid and insulin concentrations caused by the HFD. Baicalin also suppressed systemic inflammation by reducing the serum level of tumor necrosis factor α. Baicalin reduced hepatic lipid accumulation, enhanced the phosphorylation of AMPK and ACC and down-regulated genes involved in lipogenesis, including fatty acid synthase and its upstream regulator SREBP-1c. In HepG2 cells, baicalin (5 and 10 µmol/L) increased the phosphorylation of AMPK and decreased lipid accumulation following the addition of high glucose. Conclusion: Our study suggests that baicalin might have beneficial effects on the development of hepatic steatosis and obesity-related disorders by targeting the hepatic AMPK.

show abstract

“…It has also been shown, that pharmacological activation of AMPK can be achieved by metformin, a drug widely used for the treatment of type 2 diabetes mellitus (21).…”

Section: Introductionmentioning

confidence: 99%

Prognostic impact of AMP-activated protein kinase expression in ovarian carcinoma: Correlation of protein expression and GC/TOF-MS-based metabolomics

et al. 2011

View full text Add to dashboard Cite

Abstract. AMP-activated protein kinase (AMPK) plays a central role in regulating energy metabolism in cells. AMPK activation results in down-regulation of anabolic pathways (e.g., fatty acid biosynthesis) and switches on catabolic processes such as glucose uptake, glycolysis or fatty acid oxidation. Recent studies in cell culture models have shown that the growth of tumor cell lines was inhibited by AMPK activation, but the expression of AMPK in human ovarian tumors has not been reported so far. In this study we investigated AMPK expression in a cohort of 70 ovarian carcinomas, 14 borderline tumors and 5 normal ovaries and linked the protein expression data to Gas chromatography/ time of flight mass spectrometry (GC/TOF-MS) based metabolomics. We observed a significantly higher expression in ovarian carcinomas compared to borderline tumors and normal ovaries (p=0.038). Decreased AMPK expression correlated significantly with higher tumor grade (p=0.009) and was of adverse prognosis in patients with advanced tumor stages (p=0.016) as well as in patients with serous ovarian carcinomas (p=0.037). GC/TOF-MS based metabolomics revealed a significantly higher concentration of glucose in AMPK-negative carcinomas (p=0.022) as well as overexpression of other metabolites from carbohydrate metabolism. Our results indicate a role for AMPK in progression of ovarian tumors and point towards a prognostic impact of AMPK expression for patient overall survival. Furthermore, our data suggest a deregulation of the AMPK-dependent energy metabolism in human ovarian carcinomas. In future clinical studies, activation of AMPK in ovarian carcinoma patients with advanced tumor stages might be an interesting therapeutic approach.

show abstract

AMP activated protein kinase: a next generation target for total metabolic control

Cited by 104 publications

References 82 publications

Metformin Activates AMP Kinase through Inhibition of AMP Deaminase

Metformin Activates AMP Kinase through Inhibition of AMP Deaminase

Long-term baicalin administration ameliorates metabolic disorders and hepatic steatosis in rats given a high-fat diet

Prognostic impact of AMP-activated protein kinase expression in ovarian carcinoma: Correlation of protein expression and GC/TOF-MS-based metabolomics

Contact Info

Product

Resources

About