Metformin sensitizes insulin signaling through AMPK‐mediated pten down‐regulation in preadipocyte 3T3‐L1 cells

Lee, Soo Kyung; Lee, Jung Ok; Kim, Ji Hae; Kim, Su Jin; You, Ga Young; Moon, Ji Wook; Jung, Jin Hee; Park, Sun Hwa; Uhm, Kyung Ok; Park, Ji‐Man; Suh, Pann Ghill; Kim, Hyeon Soo

doi:10.1002/jcb.23000

Cited by 52 publications

(28 citation statements)

References 39 publications

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“…We demonstrated that a reciprocal relationship exists between AMPK and PTEN in the L-carnitine-mediated activation of PPARα in carboplatin-treated RTCs. These findings are consistent with those of a previous study, which showed that metformin, an insulin-sensitizing drug, suppressed the expression of PTEN through an AMPK-dependent mechanism in preadipocyte 3T3-L1 cells [39]. By contrast, AMPK knockdown eliminated the effects of metformin on reducing PTEN, suggesting that AMPK is involved in the regulation of PTEN.…”

Section: Discussionsupporting

confidence: 93%

L-Carnitine Protects against Carboplatin-Mediated Renal Injury: AMPK- and PPARα-Dependent Inactivation of NFAT3

et al. 2014

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We have previously shown that carboplatin induces inflammation and apoptosis in renal tubular cells (RTCs) through the activation of the nuclear factor of activated T cells-3 (NFAT3) protein by reactive oxygen species (ROS), and that the ROS-mediated activation of NFAT3 is prevented by N-acetyl cysteine and heme oxygenase-1 treatment. In the current study, we investigated the underlying molecular mechanisms of the protective effect of L-carnitine on carboplatin-mediated renal injury. Balb/c mice and RTCs were used as model systems. Carboplatin-induced apoptosis in RTCs was examined using terminal-deoxynucleotidyl-transferase-mediated dUTP nick end labeling. We evaluated the effects of the overexpression of the peroxisome-proliferator-activated receptor alpha (PPARα) protein, the knockdown of PPARα gene, and the blockade of AMPK activation and PPARα to investigate the underlying mechanisms of the protective effect of L-carnitine on carboplatin-mediated renal injury. Carboplatin reduced the nuclear translocation, phosphorylation, and peroxisome proliferator responsive element transactivational activity of PPARα. These carboplatin-mediated effects were prevented by L-carnitine through a mechanism dependent on AMPK phosphorylation and subsequent PPARα activation. The activation of PPARα induced cyclooxygenase 2 (COX-2) and prostacyclin (PGI2) synthase expression that formed a positive feedback loop to further activate PPARα. The coimmunoprecipitation of the nuclear factor (NF) κB proteins increased following the induction of PPARα by L-carnitine, which reduced NFκB transactivational activity and cytokine expression. The in vivo study showed that the inactivation of AMPK suppressed the protective effect of L-carnitine in carboplatin-treated mice, indicating that AMPK phosphorylation is required for PPARα activation in the L-carnitine-mediated protection of RTC apoptosis caused by carboplatin. The results of our study provide molecular evidence that L-carnitine prevents carboplatin-mediated apoptosis through AMPK-mediated PPARα activation.

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Section: Discussionsupporting

confidence: 93%

L-Carnitine Protects against Carboplatin-Mediated Renal Injury: AMPK- and PPARα-Dependent Inactivation of NFAT3

et al. 2014

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“…Metformin has well-established actions as an insulin and leptin sensitizer, in addition to its more recent characterization as an incretin sensitizer in the ␤-cell (36,59,60). Therefore, we also investigated the effects of metformin as an L cell sensitizer in vitro, using the same timeframe (i.e.…”

Section: Discussionmentioning

confidence: 97%

Mechanisms Underlying Metformin-Induced Secretion of Glucagon-Like Peptide-1 from the Intestinal L Cell

et al. 2011

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Glucagon-like peptide-1(7-36NH2) (GLP-1) is secreted by the intestinal L cell in response to both nutrient and neural stimulation, resulting in enhanced glucose-dependent insulin secretion. GLP-1 is therefore an attractive therapeutic for the treatment of type 2 diabetes. The antidiabetic drug, metformin, is known to increase circulating GLP-1 levels, although its mechanism of action is unknown. Direct effects of metformin (5-2000 μm) or another AMP kinase activator, aminoimidazole carboxamide ribonucleotide (100-1000 μm) on GLP-1 secretion were assessed in murine human NCI-H716, and rat FRIC L cells. Neither agent stimulated GLP-1 secretion in any model, despite increasing AMP kinase phosphorylation (P < 0.05-0.01). Treatment of rats with metformin (300 mg/kg, per os) or aminoimidazole carboxamide ribonucleotide (250 mg/kg, sc) increased plasma total GLP-1 over 2 h, reaching 37 ± 9 and 29 ± 9 pg/ml (P < 0.001), respectively, compared with basal (7 ± 1 pg/ml). Plasma activity of the GLP-1-degrading enzyme, dipeptidylpeptidase-IV, was not affected by metformin treatment. Pretreatment with the nonspecific muscarinic antagonist, atropine (1 mg/kg, iv), decreased metformin-induced GLP-1 secretion by 55 ± 11% (P < 0.05). Pretreatment with the muscarinic (M) 3 receptor antagonist, 1-1-dimethyl-4-diphenylacetoxypiperidinium iodide (500 μg/kg, iv), also decreased the GLP-1 area under curve, by 48 ± 8% (P < 0.05), whereas the antagonists pirenzepine (M1) and gallamine (M2) had no effect. Furthermore, chronic bilateral subdiaphragmatic vagotomy decreased basal secretion compared with sham-operated animals (7 ± 1 vs. 13 ± 1 pg/ml, P < 0.001) but did not alter the GLP-1 response to metformin. In contrast, pretreatment with the gastrin-releasing peptide antagonist, RC-3095 (100 μg/kg, sc), reduced the GLP-1 response to metformin, by 55 ± 6% (P < 0.01) at 30 min. These studies elucidate the mechanism underlying metformin-induced GLP-1 secretion and highlight the benefits of using metformin with dipeptidylpeptidase-IV inhibitors in patients with type 2 diabetes.

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“…Our results show the involvement of PTEN on TNF-α-induced reduced vascular insulin responses. There is evidence showing that PTEN modulates hyperglycemia and insulin resistance [54]. In addition, PTEN deletion in pancreatic α-cells protects against HFD-induced insulin resistance [55].…”

Section: Discussionmentioning

confidence: 99%

TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice

Costa

Neves

Mestriner

et al. 2016

Cardiovasc Diabetol

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BackgroundHigh fat diet (HFD) induces insulin resistance in various tissues, including the vasculature. HFD also increases plasma levels of TNF-α, a cytokine that contributes to insulin resistance and vascular dysfunction. Considering that the enzyme phosphatase and tension homologue (PTEN), whose expression is increased by TNF-α, reduces Akt signaling and, consequently, nitric oxide (NO) production, we hypothesized that PTEN contributes to TNF-α-mediated vascular resistance to insulin induced by HFD. Mechanisms underlying PTEN effects were determined.MethodsMesenteric vascular beds were isolated from C57Bl/6J and TNF-α KO mice submitted to control or HFD diet for 18 weeks to assess molecular mechanisms by which TNF-α and PTEN contribute to vascular dysfunction.ResultsVasodilation in response to insulin was decreased in HFD-fed mice and in ex vivo control arteries incubated with TNF-α. TNF-α receptors deficiency and TNF-α blockade with infliximab abolished the effects of HFD and TNF-α on insulin-induced vasodilation. PTEN vascular expression (total and phosphorylated isoforms) was increased in HFD-fed mice. Treatment with a PTEN inhibitor improved insulin-induced vasodilation in HFD-fed mice. TNF-α receptor deletion restored PTEN expression/activity and Akt/eNOS/NO signaling in HFD-fed mice.ConclusionTNF-α induces vascular insulin resistance by mechanisms that involve positive modulation of PTEN and inhibition of Akt/eNOS/NO signaling. Our findings highlight TNF-α and PTEN as potential targets to limit insulin resistance and vascular complications associated with obesity-related conditions.

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Metformin sensitizes insulin signaling through AMPK‐mediated pten down‐regulation in preadipocyte 3T3‐L1 cells

Cited by 52 publications

References 39 publications

L-Carnitine Protects against Carboplatin-Mediated Renal Injury: AMPK- and PPARα-Dependent Inactivation of NFAT3

L-Carnitine Protects against Carboplatin-Mediated Renal Injury: AMPK- and PPARα-Dependent Inactivation of NFAT3

Mechanisms Underlying Metformin-Induced Secretion of Glucagon-Like Peptide-1 from the Intestinal L Cell

TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice

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