bims-amsmem Biomed News
on AMPK signaling mechanism in energy metabolism
Issue of 2022‒12‒04
eleven papers selected by
Dipsikha Biswas, Københavns Universitet
  1. Quinacrine attenuates diet-induced obesity by inhibiting adipogenesis via activation of AMPK signaling.
  2. Activated AMPK Protects Against Chronic Cerebral Ischemia in Bilateral Carotid Artery Stenosis Mice.
  3. X-box binding protein 1: A new metabolic mediator and drug target of metformin?
  4. A Subset of VEGFR-TKIs Activates AMPK in LKB1-mutant Lung Cancer.
  5. Developmental endothelial locus-1 attenuates palmitate-induced apoptosis in tenocytes through the AMPK/autophagy-mediated suppression of inflammation and endoplasmic reticulum stress.
  6. 5'AMP-activated protein kinase: an emerging target of phytochemicals to treat chronic inflammatory diseases.
  7. A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.
  8. AMPK/Drp1 pathway mediates Streptococcus uberis-Induced mitochondrial dysfunction.
  9. AMPK activator decelerates osteoarthritis development by inhibition of β-catenin signaling in chondrocytes.
  10. Chlorogenic acid improves food allergy through the AMPK/ACC/CPT-1 pathway.
  11. PGC-1α Affects Epileptic Seizures by Regulating Mitochondrial Fusion in Epileptic Rats.
  1. Eur J Pharmacol. 2022 Nov 29. pii: S0014-2999(22)00693-8. [Epub ahead of print] 175432
    Quinacrine attenuates diet-induced obesity by inhibiting adipogenesis via activation of AMPK signaling.
    Xiangxiang Li, Jing Zhou, Zhuozhou Hu, Liang Han, Wenyang Zhao, Tongyu Wu, Chun Li, Jingjing Liu, Jia Kang, Xinping Chen.
      Obesity, a global epidemic chronic metabolic disease, urgently demands novel therapies. As an antimalarial drug, quinacrine has not been reported for its anti-obesity effect to our knowledge. This study aimed to explore the ability of quinacrine to attenuate obesity. In an in vitro adipogenic model, quinacrine exhibited an outstanding suppression on adipogenesis of 3T3-L1 cells, mainly by activating the AMPK (Adenosine 5'-monophosphate (AMP)-activated protein kinase) signaling pathway to regulate preadipocytes differentiation and lipid accumulation. In addition, C57BL/6N female mice were fed with high-fat diet and high-fructose water for 14 weeks to establish an obesity model, followed by oral administration of quinacrine or orlistat. After 9 weeks of treatment, quinacrine significantly reduced the body weight and energy intake, ameliorated the impaired glucose tolerance and restored the homeostasis of serum lipids. Also, quinacrine improved lipid profile and optimized the expression of AMPK signaling pathway related proteins in livers and adipose tissues of obese mice. Quinacrine reverses obesity through activating AMPK phosphorylation to down-regulate adipogenesis, along with lowering the risk of type 2 diabetes and atherosclerosis. It should be a novel application for the treatment of obesity and its associated diseases.
    Keywords:  3T3-L1 adipocytes; AMPK; Adipogenesis; High-fat diet; Obesity; Quinacrine
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175432
  2. Cell Mol Neurobiol. 2022 Nov 28.
    Activated AMPK Protects Against Chronic Cerebral Ischemia in Bilateral Carotid Artery Stenosis Mice.
    Weijie Xie, Yanqin Zeng, Yunqiu Zheng, Bin Cai.
      AMP-activated protein kinase (AMPK) is a regulator of cellular energy metabolism. Long-term use of metformin, an AMPK activator, was previously reported to be neuroprotective, as it promotes behavioral improvement and angiogenesis following an acute ischemic injury of the brain. However, only a few studies have demonstrated the role of AMPK in alleviating chronic cerebral ischemia (CCI) in mice models in the long-term (over 3 months). Therefore, we established a mouse model of CCI via bilateral carotid artery stenosis (BCAS) to explore the effect of AMPK on CCI. We used four groups of 3-month-old male C57BL/6 mice labeled as Sham, BCAS, BCAS + metformin treatment (BCAS + Met) and BCAS + AMPKα2 gene knockout (BCAS + KO). Three months after BCAS, we measured the AMPK protein expression, spatial learning and memory, Nissl bodies, cell apoptosis, astrocyte activation, and oligodendrocyte maturation. Additionally, we observed the brain tissues for changes in cell morphology. We observed that mice in the BCAS group had impaired spatial learning and memory compared with those in the sham group. The brain tissues of mice with CCI injury showed altered cell morphology, fewer Nissl bodies, cerebral cells apoptosis, and astrocyte activation. Interestingly, compared with mice from the BCAS group, the brains of mice from BCAS + Met group suffered lesser damage, whereas those of mice from the BCAS + KO group suffered more damage. The activation of AMPK, especially AMPKα2, plays a neuroprotective role during CCI in a mouse model of BCAS.
    Keywords:  AMP-activated protein kinase (AMPK); Chronic cerebral ischemia (CCI); Gene knockout; Metformin; Mice
    DOI:  https://doi.org/10.1007/s10571-022-01312-6
  3. Front Pharmacol. 2022 ;13 1013218
    X-box binding protein 1: A new metabolic mediator and drug target of metformin?
    Kai Lou, Pei Sun, Chunxue Zhang, Qiang Jiang, Shuguang Pang.
      Accumulating evidence has demonstrated that metformin improved hypertriglyceridemia. The present study aim to investigate the molecular mechanism by which metformin improves hypertriglyceridemia via regulation of diacylglycerol O-acyltransferase 2 (DGAT2) and X-box binding protein 1 (XBP1) in the liver and whether AMP-activated protein kinase (AMPK) is involved. Mice were fed a high-fat diet (HFD) or high-fat diet with metformin for 5 weeks to evaluate the effect of metformin on triglyceride (TG) levels and expression of DGAT2 and XBP1 in the liver. In vitro HepG2 cells or XBP1 knockout AML12 hepatocytes were stimulated with metformin, palmitic acid or small interfering RNA inducing XBP1 knockdown, or dominant-negative mutant AMPK plasmid. Metformin treatment reduced hepatic TG levels in the liver of HFD-fed mice. Expression of nuclear and cytoplasmic XBP1 protein and its downstream target gene DGAT2 decreased in the liver of HFD-fed mice and HepG2 cells after metformin treatment. AMPK inactivation or overexpression of XBP1 attenuates this effect. Our preliminary results demonstrate that metformin activates AMPK to reduce TG synthesis by inhibiting the XBP1-mediated DGAT2 pathway, at least in part, suggesting that XBP1 is a new metabolic mediator for metformin treatment of hypertriglyceridemia and associated metabolic disease.
    Keywords:  AMP-activated protein kinase; X-box binding protein 1; diacylglycerol O-acyltransferase 2; hypertriglyceridemia; metformin
    DOI:  https://doi.org/10.3389/fphar.2022.1013218
  4. Cancer Sci. 2022 Dec 02.
    A Subset of VEGFR-TKIs Activates AMPK in LKB1-mutant Lung Cancer.
    Lujie Yang, Qin Zhang, Yanli Xiong, Zhaoqian Dang, He Xiao, Qian Chen, Xiaoyan Dai, Lei Zhang, Jianwu Zhu, Dong Wang, Mengxia Li.
      The mutation of tumor suppressor gene liver kinase B1 (LKB1) has a prevalence of about 20% in non-small cell lung cancer (NSCLC). LKB1-mutant lung cancer is characterized by enhanced aggressiveness and immune escape, and is associated with poor prognosis. Therefore, it is urgent to develop effective therapeutic methods for LKB1-mutant NSCLC. Recently, apatinib, a VEGFR-TKI, was found to significantly improve the outcome of LKB1-mutant NSCLC, but the mechanism is not completely clear. In this study, AMP-activated protein kinase (AMPK), the crucial down-stream kinase of LKB1 was excavated as the potential target of apatinib. Biochemical experiments verified that apatinib is a direct AMPK activator. Moreover, clinically available VEGFR-TKIs were found to regulate AMPK differently that, apatinib and anlotinib can directly activate AMPK, while axitinib and sunitinib can directly inhibit AMPK. Activation of AMPK by apatinib leads to the phosphorylation of acetyl-CoA carboxylase (ACC) and inhibition of de novo fatty acid synthesis (FAsyn), which is up-regulated in LKB1-null cancers. Moreover, the killing effect of apatinib was obviously enhanced under delipidated condition, and the combination of exogenous FA restriction with apatinib treatment can be a promising method for treating LKB1-mutant NSCLC. This study discovered AMPK as an important off-target of apatinib, and elucidated different effects of this cluster of VEGFR-TKIs on AMPK. This finding can be the basis for the accurate and combined application of these drugs in clinic, and highlights the subset of VEGFR-TKIs including apatinib and anlotinib are potentially valuable in the treatment of LKB1-mutant NSCLC.
    Keywords:  AMPK; Lung cancer; STK11; VEGFR-TKI; fatty acid metabolism
    DOI:  https://doi.org/10.1111/cas.15677
  5. Bone Joint Res. 2022 Dec;11(12): 854-861
    Developmental endothelial locus-1 attenuates palmitate-induced apoptosis in tenocytes through the AMPK/autophagy-mediated suppression of inflammation and endoplasmic reticulum stress.
    Tae J Park, Seung Y Park, Wonjun Cho, Heeseung Oh, Hyun J Lee, A M Abd El-Aty, Cemil Bayram, Ji H Jeong, Tae W Jung.
      AIMS: Myokine developmental endothelial locus-1 (DEL-1) has been documented to alleviate inflammation and endoplasmic reticulum (ER) stress in various cell types. However, the effects of DEL-1 on inflammation, ER stress, and apoptosis in tenocytes remain unclear.METHODS: Human primary tenocytes were cultured in palmitate (400 μM) and palmitate plus DEL-1 (0 to 2 μg/ml) conditions for 24 hours. The expression levels of ER stress markers and cleaved caspase 3, as well as phosphorylated 5' adenosine monophosphate-activated protein kinase (AMPK) and autophagy markers, were assessed by Western blotting. Autophagosome formation was measured by staining with monodansylcadaverine, and apoptosis was determined by cell viability assay and caspase 3 activity assay.
    RESULTS: We found that treatment with DEL-1 suppressed palmitate-induced inflammation, ER stress, and apoptosis in human primary tenocytes. DEL-1 treatment augmented LC3 conversion and p62 degradation as well as AMPK phosphorylation. Moreover, small interfering RNA for AMPK or 3-methyladenine (3-MA), an autophagy inhibitor, abolished the suppressive effects of DEL-1 on inflammation, ER stress, and apoptosis in tenocytes. Similar to DEL-1, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMPK, also attenuated palmitate-induced inflammation, ER stress, and apoptosis in tenocytes, which 3-MA reversed.
    CONCLUSION: These results revealed that DEL-1 suppresses inflammation and ER stress, thereby attenuating tenocyte apoptosis through AMPK/autophagy-mediated signalling. Thus, regular exercise or administration of DEL-1 may directly contribute to improving tendinitis exacerbated by obesity and insulin resistance.Cite this article: Bone Joint Res 2022;11(12):854-861.
    Keywords:  AMPK; Apoptosis; Autophagy; DEL-1; ER stress; Obesity; RNA; Tenocytes; Western blotting; apoptosis; autophagy; caspase 3; inflammation; insulin; staining; tendinitis
    DOI:  https://doi.org/10.1302/2046-3758.1112.BJR-2022-0077.R2
  6. Crit Rev Food Sci Nutr. 2022 Nov 30. 1-26
    5'AMP-activated protein kinase: an emerging target of phytochemicals to treat chronic inflammatory diseases.
    Hafiz Abdul Khaliq, Mireille Alhouayek, Joëlle Quetin-Leclercq, Giulio G Muccioli.
      Inflammation is a defensive response of the organism to traumatic, infectious, toxic, ischemic, and autoimmune injury. Inflammatory mediators are released to effectively eliminate the inflammatory trigger and restore homeostasis. However, failure of these processes can lead to chronic inflammatory conditions and diseases such as inflammatory bowel diseases, rheumatoid arthritis, inflammatory lung diseases, atherosclerosis, and neurodegenerative diseases. The cure of chronic inflammatory diseases remains challenging as current therapies have various limitations, such as pronounced side effects, progressive loss of efficacy, and high cost especially for biologics. In this context, phytochemicals (such as alkaloids, flavonoids, lignans, phenolic acids, saponins, terpenoids, and other classes) are considered as an interesting alternative approach. Among the numerous targets of phytochemicals, AMP-activated protein kinase (AMPK) can be considered as an interesting target in the context of inflammation. AMPK regulates inflammatory response by inhibiting inflammatory pathways (NF-κB, JAK/STAT, and MAPK) and regulating several other processes of the inflammatory response (oxidative stress, autophagy, and apoptosis). In this review, we summarize and discuss the studies focusing on phytochemicals that showed beneficial effects by blocking different inflammatory pathways implicating AMPK activation in chronic inflammatory disease models. We also highlight elements to consider when investigating AMPK in the context of phytochemicals.
    Keywords:  AICAR; ARDS; Dorsomorphin; acute lung injury; curcuminoids; stilbenoids
    DOI:  https://doi.org/10.1080/10408398.2022.2145264
  7. Pharmacol Res. 2022 Nov 23. pii: S1043-6618(22)00524-2. [Epub ahead of print]187 106578
    A positive feedback loop between AMPK and GDF15 promotes metformin antidiabetic effects.
    David Aguilar-Recarte, Emma Barroso, Meijian Zhang, Patricia Rada, Javier Pizarro-Delgado, Lucía Peña, Xavier Palomer, Ángela M Valverde, Walter Wahli, Manuel Vázquez-Carrera.
      BACKGROUND AND AIMS: Metformin, the most prescribed drug for the treatment of type 2 diabetes mellitus, has been recently reported to promote weight loss by upregulating the anorectic cytokine growth differentiation factor 15 (GDF15). Since the antidiabetic effects of metformin are mostly mediated by the activation of AMPK, a key metabolic sensor in energy homeostasis, we examined whether the activation of this kinase by metformin was dependent on GDF15.METHODS: Cultured hepatocytes and myotubes, and wild-type and Gdf15-/- mice were utilized in a series of studies to investigate the involvement of GDF15 in the activation of AMPK by metformin.
    RESULTS: A low dose of metformin increased GDF15 levels without significantly reducing body weight or food intake, but it ameliorated glucose intolerance and activated AMPK in the liver and skeletal muscle of wild-type mice but not Gdf15-/- mice fed a high-fat diet. Cultured hepatocytes and myotubes treated with metformin showed AMPK-mediated increases in GDF15 levels independently of its central receptor GFRAL, while Gdf15 knockdown blunted the effect of metformin on AMPK activation, suggesting that AMPK is required for the metformin-mediated increase in GDF15, which in turn is needed to sustain the full activation of this kinase independently of the CNS.
    CONCLUSION: Overall, these findings uncover a novel mechanism through which GDF15 upregulation by metformin is involved in achieving and sustaining full AMPK activation by this drug independently of the CNS.
    Keywords:  AMPK; GDF15; Glucose tolerance; Metformin
    DOI:  https://doi.org/10.1016/j.phrs.2022.106578
  8. Int Immunopharmacol. 2022 Dec;pii: S1567-5769(22)00897-9. [Epub ahead of print]113(Pt A): 109413
    AMPK/Drp1 pathway mediates Streptococcus uberis-Induced mitochondrial dysfunction.
    Yuanyuan Zhou, Ming Li, Zhenglei Wang, Xinguang Lin, Yuanyuan Xu, Shiyuan Feng, Jinfeng Miao.
      Excessive production of reactive oxygen species (ROS) leads to oxidative stress in host cells and affects the progress of disease. Mitochondria are an important source of ROS and their dysfunction is closely related to ROS production. S. uberis is a common causative agent of mastitis. The expression of key enzymes of the mitochondrial apoptotic pathway is increased in mammary epithelial cells after S. uberis stimulation, while expression of proteins related to mitochondrial function is decreased. Drp1, a key protein associated with mitochondrial function, is activated upon infection. Accompanied by mitochondria-cytosol translocation of Drp1, Fis1 expression is significantly upregulated while Mfn1 expression is downregulated implying that the balance of mitochondrial dynamics is disrupted. This leads to mitochondrial fragmentation, decreased mitochondrial membrane potential, higher levels of mROS and oxidative injury. The AMPK activator AICAR inhibits the increased phosphorylation of Drp1 and the translocation of Drp1 to mitochondria by salvaging mitochondrial function in an AMPK/Drp1 dependent manner, which has a similar effect to Drp1 inhibitor Mdivi-1. These data show that AMPK, as an upstream negative regulator of Drp1, ameliorates mitochondrial dysfunction induced by S. uberis infection.
    Keywords:  AMPK; Drp1; Mitochondria; Streptococcus uberis
    DOI:  https://doi.org/10.1016/j.intimp.2022.109413
  9. J Orthop Translat. 2023 Jan;38 158-166
    AMPK activator decelerates osteoarthritis development by inhibition of β-catenin signaling in chondrocytes.
    Zhenglin Zhu, Yanran Huang, Jun Li, Dan Yi, Junyi Liao, Jun Xiao, Guozhi Xiao, Liping Tong, Wei Huang, Chen Di.
      Background: Osteoarthritis (OA) is a common degenerative joint disease with significant negative impact on the quality of life. It has been reported that abnormal upregulation of β-catenin signaling could lead to OA development; however, the upstream regulatory mechanisms of β-catenin signaling have not been determined.Methods: Primary rat chondrocytes and ATDC5 chondrocyte cell line were stimulated with AKT2 and treated with or without metformin, an adenosine 5'-monophosphate-activated protein kinase (AMPK) activator. Westerrn blot analysis, luciferase reporter assay and immunofluorescent (IF) staining were performed to examine changes in β-cateninS552 phosphorylation and β-catenin nuclear translocation in ATDC5 cells and in primary chondrocytes.
    Results: We found that metformin inhibited β-cateninS552 phosphorylation in ATDC5 cells and in primary chondrocytes in a time-dependent manner. Metformin inhibited β-catenin nuclear translocation and β-catenin reporter activity. In addition, metformin also attenuated the expression of β-catenin downstream target genes. We also demonstrated that metformin inhibited β-cateninS552 phosphorylation in articular cartilage in mice.
    Conclusion: These findings suggest that metformin may exert its chondro-protective effect at least in part through the inhibition of β-catenin signaling in chondrocytes.
    The translational potential of this article: This study demonstrated the interaction between AMPK and β-catenin signaling in chondrocytes and defined novel molecular targets for the treatment of OA disease.
    Keywords:  AMPK; Chondrocyte; Metformin; Osteoarthritis; Osteoarthritis, OA; Phosphorylation; β-catenin
    DOI:  https://doi.org/10.1016/j.jot.2022.10.005
  10. J Food Biochem. 2022 Dec 01. e14505
    Chlorogenic acid improves food allergy through the AMPK/ACC/CPT-1 pathway.
    Ze Yun, Zhiying Zou, Shanfeng Sun, Huilian Che.
      Chlorogenic acid (CGA) is a polyphenol prevalent in daily food and plants. Food allergy (FA) can lead to metabolic disorders of the immune system. The objective of this study was to investigate CGA therapeutic effect on FA and regulatory mechanism through shrimp food allergy in mice models. Here, 24 female BALB/C mice were randomly allocated into the (I) Control group, (II) Food allergy group, (III) Chlorogenic acid low (50 mg/kg), and (IV) high group (200 mg/kg). Enzyme-linked immunosorbent assay revealed that CGA decreased levels of IgE and IgG induced by food allergy significantly. Real-time PCR demonstrated that high-dose chlorogenic acid significantly reduced Acetyl-CoA carboxylase (ACC) mRNA expression and increased Carnitine palmitoyltransferase-1 (CPT-1) mRNA expression. Western blot indicated that CGA promoted a noticeable increase at the levels of AMP-activated protein kinase (AMPK) and ACC phosphorylation, resulting in a significant activation in AMPK and inhibition in ACC, and increased CPT-1 expression. Consequently, CGA improves FA by the regulation of the AMPK/ACC/CPT-1 signaling pathway in the spleen. PRACTICAL APPLICATIONS: Chlorogenic acid is a water-soluble polyphenolic substance that is widely distributed in natural plants that show a variety of pharmacological effects. At present, CGA has been developed as a weigh-reducing tonic in western countries. As one of the most widely found and most easily obtained phenolic acids from food, the diverse physiological effects of CGA (such as anti-inflammatory, antioxidant, metabolic regulation, intestinal microbial regulation, etc.) imply its potential for application in functional foods, food additives, and clinical medicine. However, the basic molecular mechanisms of its effects have not been elucidated. In this study, CGA reduced allergy in a mouse model, likely by interacting with the AMPK/ACC/CPT-1 pathway.
    Keywords:  AMP-activated protein kinase; acetyl-CoA carboxylase; carnitine palmitoyltransferase-1; chlorogenic acid; food allergy
    DOI:  https://doi.org/10.1111/jfbc.14505
  11. Neurochem Res. 2022 Dec 01.
    PGC-1α Affects Epileptic Seizures by Regulating Mitochondrial Fusion in Epileptic Rats.
    Dongxu Li, Linhai Zhang, Jinmei Tuo, Fan Zhang, Zhenzhen Tai, Xiping Liu, Xiaowei Qiu, Haiqing Zhang, Juan Yang, Jing Wang, Zhong Luo, Zucai Xu.
      BACKGROUND: Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), regulated by AMPK, is an important regulator of mitochondrial fusion. At present, whether the AMPK/PGC-1α signaling pathway regulates mitochondrial dynamics in epileptic rats is still unknown.METHODS: Adult male Sprague-Dawley (SD) rats were randomly divided into fourgroups: the control group (0.9% saline, n = 5), the EP groups (lithium-pilocarpine was used to induce epilepsy, and tissues were harvested at 6 and 24 h, every time point, n = 5), the EP + Compound C group (the specific inhibitor of PGC-1α, 15 mg/kg in 2% DMSO, n = 5), and the EP + DMSO group (0.9% saline + 2% DMSO, n = 5). To investigate whether PGC-1α participates in seizures by regulating the expression of mitofusin1/2(MFN1/2)in rats.
    RESULTS: In this study, the behavioral results indicate that the seizure susceptibility of the rats to epilepsy was increased when the expression of PGC-1α was inhibited. Subsequently, Western blot results suggested that the expression level of both MFN1 and MFN2 in the hippocampus was higher at 6 and 24 h after an epileptic seizure. Besides, the expression of PGC-1α and MFN2 was significantly decreased in the hippocampus when the epileptic rats were treated with Compound C. Furthermore, the immunofluorescence analysis of the localization of MFN1/2 and PGC-1α showed that MFN1/2 was mainly expressed in neurons but not astrocytes in the hippocampus and cerebral cortex of rats. Meanwhile, PGC-1α colocalized with the excitatory post-synaptic marker PSD95, suggesting that PGC-1α may regulate the seizure susceptibility of the rats by mediating excitatory post-synaptic signaling.
    CONCLUSION: The AMPK/PGC-1α signaling pathway may play an important role in the lithium-pilocarpine-induced epileptic rat model by mediating the expression of fusion proteins.
    Keywords:  AMPK; Compound C; Epilepsy; MFN1/2; PGC-1α
    DOI:  https://doi.org/10.1007/s11064-022-03834-3
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