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....

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Cell reports (Cambridge) Ročník 29; číslo 6; s. 1511 - 1523.e5
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 05.11.2019 Elsevier
Témata:	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 membrane potential metformin AMPK mitochondrial respiration/fission adenine nucleotides diabetes insulin resistance Drp1
ISSN:	2211-1247, 2211-1247
On-line přístup:	Získat plný text
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 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
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2019.09.070