Inhibition of mitochondrial fission by Drp-1 blockade by short-term leptin and Mdivi-1 treatment improves white adipose tissue abnormalities in obesity and diabetes. (April 2022)

• Record Type: Journal Article
• Authors: Finocchietto, P.; Perez, H.; Blanco, G.; Miksztowicz, V.; Marotte, C.; Morales, C.; Peralta, J.; Berg, G.; Poderoso, C.; Poderoso, J.J.; Carreras, M.C.
• Is Part Of: Pharmacological research. Volume 178(2022)
• Publication Date: 2022-04
• Subjects: AMPK AMP-dependent kinase -- BAT brown adipose tissue -- DAF-FM amino-5-methylamino-2¢, 7¢-difluorofluorescein diacetate -- DRP-1 dynamin-related protein-1 -- FFA free fatty acid -- LC3-II microtubule-associated protein 1A/1B-light chain 3 -- Mdivi-1 selective inhibitor of Drp1 -- Mfn2 mitofusin proteins -- NO nitric oxide -- NRF1 nuclear respiratory factor -- Ob/ob leptin-deficient mice -- OPA-1 optic atrophy-1 -- OXPHOS oxidative phosphorylation system -- PE phosphatidylethanolamine -- PGC-1α proliferator-activated receptor gamma coactivator-1 alpha -- RNS reactive nitrosative species -- ROS reactive oxygen species -- RT-PCR reverse transcription-polymerase chain reaction -- siRNA small interference RNA -- UCP-1 uncoupler protein 1 -- WAT white adipose tissue; White adipose tissue -- Mitochondria -- Biogenesis -- Dynamics -- Drp-1 -- Mdivi-1; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.106028
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Background: Obesity and type 2 diabetes are chronic diseases characterized by insulin resistance, mitochondrial dysfunction and morphological abnormalities. Objective: We have investigated if dysregulation of mitochondrial dynamics and biogenesis is involved in an animal model of obesity and diabetes. Methods: The effect of short-term leptin and mdivi-1 – a selective inhibitor of Drp-1 fission-protein – treatment on mitochondrial dynamics and biogenesis was evaluated in epididymal white adipose tissue (WAT) from male ob/ob mice. Results: An increase in Drp-1 protein levels and a decrease in Mfn2 and OPA-1 protein expression were observed with enhanced and sustained mitochondrial fragmentation in ob/ob mice compared to wt C57BL/6 animals (p < 0.05). The content of mitochondrial DNA and PGC-1α mRNA expression –both parameters of mitochondrial biogenesis– were reduced in ob/ob mice (p < 0.05). Treatment with leptin and mdivi-1 significantly increased mitochondrial biogenesis, improved fusion-to-fission balance and attenuated mitochondrial dysfunction, thus inducing white-to-beige adipocyte transdifferentiation. Measurements of glucose and lipid oxidation in adipocytes revealed that both leptin and mdivi-1 increase substrates oxidation while in vivo determination of blood glucose concentration showed decreased levels by 50% in ob/ob mice, almost to the wt level. Conclusions: Pharmacological targeting of Drp-1 fission protein may be a potential novel therapeutic tool for obesity and type 2 diabetes. Graphical Abstract: ga1 Highlights: Mitochondrial dynamic and biogenesis are abnormal in white adipose tissue in this animal model of obesity and type 2 diabetes. Drp-1 fission protein is overexpressed while the fusion- proteins are decreased in this animals. Drp-1 fission protein blocking in white adipose tissue:a new therapeutic target for obesity and diabetes. This molecule should be a new therapeutic target for obesity and type 2 diabetes.