Abstract
Background Obesity and type 2 diabetes are chronic diseases characterized by insulin resistance, mitochondrial dysfunction and morphology abnormalities.
Objective Herein, we 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 mRNA expression of PGC-1α –both parameters of mitochondrial biogenesis– were reduced in ob/ob mice (p<0.05). Leptin and mdivi-1 treatment 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.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations Used
- 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
- siRNA
- small interference RNA
- UCP-1
- uncoupler protein 1
- WAT
- white adipose tissue