Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK

Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients’ hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood....

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Published in:Cell reports (Cambridge) Vol. 29; no. 6; pp. 1511 - 1523.e5
Main Authors: Wang, Yu, An, Hongying, Liu, Ting, Qin, Caolitao, Sesaki, Hiromi, Guo, Shaodong, Radovick, Sally, Hussain, Mehboob, Maheshwari, Akhil, Wondisford, Fredric E., O’Rourke, Brian, He, Ling
Format: Journal Article
Language:English
Published: United States Elsevier Inc 05.11.2019
Elsevier
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ISSN:2211-1247, 2211-1247
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Abstract Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients’ hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5′ AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin’s anti-tumor effects. [Display omitted] •Clinically relevant metformin dose improves liver mitochondrial respiration in obesity•Pharmacological metformin increases mitochondrial respiration and fission•Supra-pharmacological metformin inhibits mitochondrial activity by ADP reduction•AMPK is required for metformin suppression of liver glucose production The mechanism of metformin action still remains controversial, in particular on mitochondrial activity and the involvement of AMPK. Wang et al. show that pharmacological metformin concentration or dose improves mitochondrial respiration by increasing mitochondrial fission through AMPK-Mff signaling; in contrast, supra-pharmacological metformin concentrations reduce mitochondrial respiration through decreasing adenine nucleotide levels.
AbstractList Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients' hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5' AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin's anti-tumor effects.Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients' hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5' AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin's anti-tumor effects.
Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients’ hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5′ AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin’s anti-tumor effects. : The mechanism of metformin action still remains controversial, in particular on mitochondrial activity and the involvement of AMPK. Wang et al. show that pharmacological metformin concentration or dose improves mitochondrial respiration by increasing mitochondrial fission through AMPK-Mff signaling; in contrast, supra-pharmacological metformin concentrations reduce mitochondrial respiration through decreasing adenine nucleotide levels. Keywords: metformin, diabetes, insulin resistance, mitochondrial respiration/fission, membrane potential, adenine nucleotides, AMPK, Drp1
Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients’ hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5′ AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin’s anti-tumor effects. The mechanism of metformin action still remains controversial, in particular on mitochondrial activity and the involvement of AMPK. Wang et al. show that pharmacological metformin concentration or dose improves mitochondrial respiration by increasing mitochondrial fission through AMPK-Mff signaling; in contrast, supra-pharmacological metformin concentrations reduce mitochondrial respiration through decreasing adenine nucleotide levels.
Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients' hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5' AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin's anti-tumor effects.
Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients’ hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5′ AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin’s anti-tumor effects. [Display omitted] •Clinically relevant metformin dose improves liver mitochondrial respiration in obesity•Pharmacological metformin increases mitochondrial respiration and fission•Supra-pharmacological metformin inhibits mitochondrial activity by ADP reduction•AMPK is required for metformin suppression of liver glucose production The mechanism of metformin action still remains controversial, in particular on mitochondrial activity and the involvement of AMPK. Wang et al. show that pharmacological metformin concentration or dose improves mitochondrial respiration by increasing mitochondrial fission through AMPK-Mff signaling; in contrast, supra-pharmacological metformin concentrations reduce mitochondrial respiration through decreasing adenine nucleotide levels.
Author He, Ling
Qin, Caolitao
Radovick, Sally
Hussain, Mehboob
Wang, Yu
An, Hongying
Maheshwari, Akhil
Guo, Shaodong
O’Rourke, Brian
Wondisford, Fredric E.
Sesaki, Hiromi
Liu, Ting
AuthorAffiliation 4 Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
5 Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
3 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
9 These authors contributed equally
6 Department of Nutrition and Food Science, Texas A&M University, TX 77843, USA
2 Division of Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
8 Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI 48105, USA
1 Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
7 Departments of Pediatrics and Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
10 Lead Contact
AuthorAffiliation_xml – name: 9 These authors contributed equally
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– name: 3 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
– name: 8 Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI 48105, USA
– name: 4 Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
– name: 10 Lead Contact
– name: 2 Division of Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
– name: 6 Department of Nutrition and Food Science, Texas A&M University, TX 77843, USA
– name: 7 Departments of Pediatrics and Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA
– name: 1 Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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  surname: Sesaki
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/31693892$$D View this record in MEDLINE/PubMed
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Issue 6
Keywords membrane potential
metformin
AMPK
mitochondrial respiration/fission
adenine nucleotides
diabetes
insulin resistance
Drp1
Language English
License This is an open access article under the CC BY-NC-ND license.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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content type line 23
L.H. designed the experiments, managed the project, and coordinated activities from all authors. Y.W., H.A., T.L., C.Q., and L.H. conducted experiments. T.L. and B.O. guided the Seahorse assays. H.S. generated and provided Drp1 KO mice. S.G. determined metabolic parameters in the blood samples. A.M. supported the analysis of the confocal images. S.R., M.H., F.E.W., and L.H. analyzed the data and wrote the manuscript.
AUTHOR CONTRIBUTIONS
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Snippet Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug,...
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SubjectTerms adenine nucleotides
Adenine Nucleotides - metabolism
AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases - genetics
AMP-Activated Protein Kinases - metabolism
AMPK
Animals
Blood Glucose - metabolism
Cell Respiration - drug effects
Cell Respiration - genetics
diabetes
Diet, High-Fat
Drp1
Electron Transport Complex I - drug effects
Electron Transport Complex I - metabolism
Gene Knockout Techniques
Hepatocytes - drug effects
Hepatocytes - metabolism
Hepatocytes - ultrastructure
Hyperglycemia - drug therapy
Hyperglycemia - genetics
Hyperglycemia - metabolism
Hypoglycemic Agents - pharmacology
Insulin Resistance
Liver - drug effects
Liver - metabolism
Liver - physiopathology
Liver - ultrastructure
membrane potential
metformin
Metformin - analysis
Metformin - pharmacology
Mice
Mice, Inbred C57BL
Mitochondria, Liver - drug effects
Mitochondria, Liver - genetics
Mitochondria, Liver - metabolism
Mitochondria, Liver - ultrastructure
Mitochondrial Dynamics - drug effects
mitochondrial respiration/fission
Protein Kinases - genetics
Protein Kinases - metabolism
Title Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK
URI https://dx.doi.org/10.1016/j.celrep.2019.09.070
https://www.ncbi.nlm.nih.gov/pubmed/31693892
https://www.proquest.com/docview/2312804482
https://pubmed.ncbi.nlm.nih.gov/PMC6866677
https://doaj.org/article/242411f041ab47b787ea101323460470
Volume 29
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