Activation of AMPKα2 in adipocytes is essential for nicotine-induced insulin resistance in vivo

Wu, Yuzhang; Song, Ping; Zhang, Wencheng; Liu, Junhui; Dai, Xiaoyan; Liu, Zhaoyu; Lu, Qiulun; Chen, Ouyang; Xie, Zhonglin; Zhao, Zhengxing; Zhuo, Xianlu; Viollet, Benoı̂t; Foretz, Marc; Wu, Jiliang; Yuan, Zuyi

doi:10.1038/nm.3826

Cited by 144 publications

(115 citation statements)

References 67 publications

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“…Numerous lines of evidence in models of diabetes, cardiovascular dysfunction, and obesity confirm the role of p38 as a possible mediator of IGFs/insulin resistance induced by oxidative stress (37)(38)(39)(40)(41)(42) and the potential benefits of its inhibition (43,44). p38 redox activation prevents IRS-1/2 phosphorylation by IGF-I or insulin, blocking in this way PI3K and AKT activation (45).…”

Section: Discussionmentioning

confidence: 92%

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Dávila

Fernández

Torres‐Alemán

2016

Journal of Biological Chemistry

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Disruption of insulin-like growth factor I (IGF-I) signaling is a key step in the development of cancer or neurodegeneration. For example, interference of the prosurvival IGF-I/AKT/ FOXO3 pathway by redox activation of the stress kinases p38 and JNK is instrumental in neuronal death by oxidative stress. However, in astrocytes, IGF-I retains its protective action against oxidative stress. The molecular mechanisms underlying this cell-specific protection remain obscure but may be relevant to unveil new ways to combat IGF-I/insulin resistance. Here, we describe that, in astrocytes exposed to oxidative stress by hydrogen peroxide (H 2 O 2 ), p38 activation did not inhibit AKT (protein kinase B) activation by IGF-I, which is in contrast to our previous observations in neurons. Rather, stimulation of AKT by IGF-I was significantly higher and more sustained in astrocytes than in neurons either under normal or oxidative conditions. This may be explained by phosphorylation of the phosphatase PTEN at the plasma membrane in response to IGF-I, inducing its cytosolic translocation and preserving in this way AKT activity. Stimulation of AKT by IGF-I, mimicked also by a constitutively active AKT mutant, reduced oxidative stress levels and cell death in H 2 O 2 -exposed astrocytes, boosting their neuroprotective action in co-cultured neurons. These results indicate that armoring of AKT activation by IGF-I is crucial to preserve its cytoprotective effect in astrocytes and may form part of the brain defense mechanism against oxidative stress injury. IGF-I2 is a pleiotropic growth factor with important prosurvival effects in neurons (1). One of the main downstream targets of IGF-I is the Ser/Thr kinase AKT (2), which mediates cell survival and proliferation (3). Upon its activation, the IGF-I receptor recruits and phosphorylates IRS docking proteins (4), which allows translocation of phosphatidylinositol 3-kinase (PI3K) to the plasma membrane where it catalyzes the formation of the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) (5). AKT is recruited to the membrane by interaction with these messengers so that it can be fully activated by PDK1 and mTORC2 kinases (3,6). This pathway is switched off (to prevent uncontrolled proliferation) through activation of the lipid and protein phosphatase PTEN, which catalyzes PIP 3 dephosphorylation (4).Cell metabolism generates potentially harmful reactive oxygen species (ROS), which at moderate levels can act as second messengers (7). However, chronic and/or abrupt increases of ROS (uncontainable by detoxification through cellular defenses) generates oxidative stress, a pathological cellular condition that can interfere with redox-sensitive signaling pathways (7). Neurons are particularly vulnerable to oxidative stress because of their low ROS detoxifying capacity (8).We previously described that oxidative stress interferes with the IGF-I/PI3K/AKT pathway by redox activation of p38 kinase to induce neuronal death (9). IGF-I signaling impairment by oxidative stress ha...

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Section: Discussionmentioning

confidence: 92%

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Dávila

Fernández

Torres‐Alemán

2016

Journal of Biological Chemistry

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“…25 Nicotine can also increase insulin resistance by activation of adenosine monophosphateactivated protein kinase. 26 In the present study, cigarette smokers showed a trend to have higher waist circumference. Previous studies have reported inconsistent results on the relationship between smoking and waist circumference.…”

Section: Discussionsupporting

confidence: 53%

Relationship of cotinine-verified and self-reported smoking status with metabolic syndrome in 116,094 Korean adults

Kim

Han

Kang

et al. 2017

Journal of Clinical Lipidology

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“…The rationale for using twice daily IP administration of nicotine (0.75 mg/kg BW) was based on the results of our previous studies, which demonstrated that this dose level of nicotine, when combined with HFD, triggered greater oxidative stress, activated hepatocellular apoptosis, amplified HFD-induced hepatic steatosis (Friedman et al 2012) and caused intramyocellular lipid accumulation and intramyofibrillar mitochondrial abnormalities in the skeletal muscle (Sinha-Hikim et al 2014). Notably, the daily dosage of 1.5 mg/kg BW in mice appeared to be similar to the clinically relevant concentrations found in habitual cigarette smokers and users of nicotine-containing chewing gum (Wu et al 2015). An additional group of five nicotine-treated mice on HFD received twice-daily IP injections of mecamylamine (1 mg/kg BW), a non-selective nicotinic acetylcholine receptor (nAChR) antagonist, for 16 weeks (Bacher et al 2009).…”

Section: Methodssupporting

confidence: 58%

Nicotine plus a high-fat diet triggers cardiomyocyte apoptosis

et al. 2016

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Cigarette smoking is an important risk factor for diabetes, cardiovascular disease and non-alcoholic fatty liver disease. The health risk associated with smoking can be aggravated by obesity. Smoking might also trigger cardiomyocyte (CM) apoptosis. Given that CM apoptosis has been implicated as a potential mechanism in the development of cardiomyopathy and heart failure, we characterize the key signaling pathways in nicotine plus high-fat diet (HFD)-induced CM apoptosis. Adult C57BL6 male mice were fed a normal diet (ND) or HFD and received twice-daily intraperitoneal (IP) injections of nicotine (0.75 mg/kg body weight [BW]) or saline for 16 weeks. An additional group of nicotine-treated mice on HFD received twice-daily IP injections of mecamylamine (1 mg/kg BW), a non-selective nicotinic acetylcholine receptor antagonist, for 16 weeks. Nicotine when combined with HFD led to a massive increase in CM apoptosis that was fully prevented by mecamylamine treatment. Induction of CM apoptosis was associated with increased oxidative stress and activation of caspase-2-mediated intrinsic pathway signaling coupled with inactivation of AMP-activated protein kinase (AMPK). Furthermore, nicotine treatment significantly (P < 0.05) attenuated the HFD-induced decrease in fibroblast growth factor 21 (FGF21) and silent information regulator 1 (SIRT1). We conclude that nicotine, when combined with HFD, triggers CM apoptosis through the generation of oxidative stress and inactivation of AMPK together with the activation of caspase-2-mediated intrinsic apoptotic signaling independently of FGF21 and SIRT1.

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Activation of AMPKα2 in adipocytes is essential for nicotine-induced insulin resistance in vivo

Cited by 144 publications

References 67 publications

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Relationship of cotinine-verified and self-reported smoking status with metabolic syndrome in 116,094 Korean adults

Nicotine plus a high-fat diet triggers cardiomyocyte apoptosis

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