Role of AMP-activated protein kinase in mechanism of metformin action

Zhou, Gaochao; Myers, Robert W.; Liu, Ying; Chen, Yuli; Shen, Xiaolan; Fenyk-Melody, Judy; Wu, Margaret; Ventre, John; Doebber, Thomas W.; Fujii, Nobuharu; Musi, Nicolas; Hirshman, Michael F.; Goodyear, Laurie J.; Moller, David E.

doi:10.1172/jci13505

Cited by 4,628 publications

(2,649 citation statements)

References 34 publications

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“…To investigate the mechanisms of the geroprotective effect of metformin on HDFs, we first investigated the most common signal pathway mediated by AMPK (Zhou et al., 2001). However, AMPK activation was not observed in HDFs treated with 100 μ m metformin (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The current consensus is that metformin targets multiple cellular signaling pathways closely associated with the development of aging, such as inflammation, cellular survival, stress defense, autophagy, and protein synthesis (Barzilai et al., 2016). One well‐accepted mechanism of metformin‐mediated lifespan extension is its ability to mimic the effects of dietary restriction through stimulating adenosine monophosphate‐activated protein kinase (AMPK), the principal energy sensor in cells, to reduce energy‐consuming processes (Martin‐Montalvo et al., 2013; Onken & Driscoll, 2010; Zhou et al., 2001). Nevertheless, whether metformin can suppress human cellular aging and the mechanisms underlying its probable geroprotective effects in humans remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

et al. 2018

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SummaryMetformin, an FDA‐approved antidiabetic drug, has been shown to elongate lifespan in animal models. Nevertheless, the effects of metformin on human cells remain unclear. Here, we show that low‐dose metformin treatment extends the lifespan of human diploid fibroblasts and mesenchymal stem cells. We report that a low dose of metformin upregulates the endoplasmic reticulum‐localized glutathione peroxidase 7 (GPx7). GP×7 expression levels are decreased in senescent human cells, and GPx7 depletion results in premature cellular senescence. We also indicate that metformin increases the nuclear accumulation of nuclear factor erythroid 2‐related factor 2 (Nrf2), which binds to the antioxidant response elements in the GPX7 gene promoter to induce its expression. Moreover, the metformin‐Nrf2‐GPx7 pathway delays aging in worms. Our study provides mechanistic insights into the beneficial effects of metformin on human cellular aging and highlights the importance of the Nrf2‐GPx7 pathway in pro‐longevity signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

et al. 2018

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“…Also, multiple lines of evidence indicate that AMPK activation suppresses the activity of sterol‐regulatory element‐binding proteins (SREBPs) that are major transcription factors activating the expression of genes involved in biosynthesis of cholesterol, fatty acids, and triglycerides (Zhou et al. 2001; Yang et al. 2008).…”

Section: Discussionmentioning

confidence: 99%

Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet

et al. 2017

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Insulin action and glucose disposal are enhanced by exercise, yet the mechanisms involved remain imperfectly understood. While the causes of skeletal muscle insulin resistance also remain poorly understood, new evidence suggest excess plasma membrane (PM) cholesterol may contribute by damaging the cortical filamentous actin (F‐actin) structure essential for GLUT4 glucose transporter redistribution to the PM upon insulin stimulation. Here, we investigated whether PM cholesterol toxicity was mitigated by exercise. Male C57BL/6J mice were placed on low‐fat (LF, 10% kCal) or high‐fat (HF, 45% kCal) diets for a total of 8 weeks. During the last 3 weeks of this LF/HF diet intervention, all mice were familiarized with a treadmill for 1 week and then either sham‐exercised (0 m/min, 10% grade, 50 min) or exercised (13.5 m/min, 10% grade, 50 min) daily for 2 weeks. HF‐feeding induced a significant gain in body mass by 3 weeks. Sham or chronic exercise did not affect food consumption, water intake, or body mass gain. Prior to sham and chronic exercise, “pre‐intervention” glucose tolerance tests were performed on all animals and demonstrated that HF‐fed mice were glucose intolerant. While sham exercise did not affect glucose tolerance in the LF or HF mice, exercised mice showed an improvement in glucose tolerance. Muscle from sham‐exercised HF‐fed mice showed a significant increase in PM cholesterol, loss of cortical F‐actin, and decrease in insulin‐stimulated glucose transport compared to sham‐exercised LF‐fed mice. These HF‐fed skeletal muscle membrane/cytoskeletal abnormalities and insulin resistance were improved in exercised mice. These data reveal a new therapeutic aspect of exercise being regulation of skeletal muscle PM cholesterol homeostasis. Further studies on this mechanism of insulin resistance and the benefits of exercise on its prevention are needed.

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“…In addition, Rapa affects glucose tolerance through inhibition of a second mTOR complex, mTORC2, resulting in hepatic insulin resistance (Lamming et al . 2013), while Met acts to activate AMPK, suppressing hepatic glucose output (DeFronzo et al ., 1991; Zhou et al ., 2001). Met would be expected to diminish the negative effects of Rapa on hepatic glucose output and thus potentially lead to a survival benefit greater than that produced by Rapa alone.…”

Section: Introductionmentioning

confidence: 99%

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

et al. 2016

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SummaryThe National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin – the latter with and without rapamycin, and two drugs previously examined: 17‐α‐estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17‐α‐estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male‐specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α‐glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.

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Role of AMP-activated protein kinase in mechanism of metformin action

Cited by 4,628 publications

References 34 publications

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

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