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Inhibition of Mitochondrial Fission by Drp-1 Blockade Improves White Adipose Tissue Abnormalities in Obesity and Diabetes
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  • Paola Finocchietto,
  • Hernan Perez,
  • Guillermo Blanco,
  • Verónica Miksztowicz,
  • Clarisa Marotte,
  • Celina Morales,
  • Jorge Peralta,
  • Gabriela Berg,
  • Cecilia Poderoso,
  • Juan Jose Poderoso,
  • Maria Cecilia Carreras
Paola Finocchietto
Hospital de Clinicas Jose de San Martin
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Hernan Perez
Hospital de Clinicas Jose de San Martin
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Guillermo Blanco
Facultad de Farmacia y Bioquímica UBA
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Verónica Miksztowicz
Facultad de Farmacia y Bioquímica UBA
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Clarisa Marotte
Hospital de Clinicas Jose de San Martin
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Celina Morales
3Institute of Cardiovascular Physiopathology, School of Medicine, University of Buenos Aires
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Jorge Peralta
Hospital de Clinicas Jose de San Martin
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Gabriela Berg
Facultad de Farmacia y Bioquímica UBA
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Cecilia Poderoso
UBA - Facultad de Medicina
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Juan Jose Poderoso
Hospital de Clinicas Jose de San Martin
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Maria Cecilia Carreras
Hospital de Clinicas Jose de San Martin
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Abstract

Background and Purpose: Obesity and Type 2 Diabetes are major causes of morbidity-mortality characterized by mitochondrial dysfunction and oxidative-nitrosative stress. Despite intensive research, the events that cause the onset and progression of these diseases are not completely understood. Herein, we investigated if dysregulation of mitochondrial dynamics and biogenesis is involved in an animal model of obesity and diabetes. Experimental Approach: Mitochondrial dynamics and biogenesis were evaluated in epididymal white adipose tissue and adipocytes from ob/ob mice, an animal model of obesity and diabetes, pharmacological treatment with mdvi-1, a selective inhibitor of Drp1 and leptin. Key Results: A decrease of Mfn2 and OPA-1 protein expression and an increase in Drp1- protein levels were observed with enhanced and sustained mitochondrial fragmentation in ob/ob mice compared to wt C57BL/6 animals. The content of mitochondrial DNA and mRNA expression of PGC-1α, both parameters of mitochondrial biogenesis, were reduced in ob/ob mice. The treatment with leptin or mdvi-1 (Drp1 inhibitor) significantly increased abnormal biogenesis, improved fusion-to-fission balance and attenuated mitochondrial dysfunction, and adipogenesis, thus inducing white-to-beige adipocyte transdifferentiation. Measurements of glucose and lipid oxidation in adipocytes revealed that both leptin and mdvi-1 increase substrates oxidation while in vivo determination of blood glucose showed decreased blood glucose concentration by 50 % in ob/ob mice, almost to the wt level. Conclusion and Implications: In light of these results, pharmacological targeting of Drp1 may be a potential novel therapeutic tool for obesity and diabetes.