Inhibition of Mitochondrial Fission by Drp-1 Blockade Improves White
Adipose Tissue Abnormalities in Obesity and Diabetes
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.