Introduction: The mitochondrion plays a critical role in cellular energy metabolism. For this
reason it is considered as a plausible target for the treatment of metabolic diseases such as obesity and
type-2 diabetes. Although several mitochondrial molecular targets have been suggested and investigated,
currently there are no marketed drugs that target the mitochondrion to treat metabolic diseases.
Through an investigation of current drugs and investigational compounds, two hypotheses have
emerged: 1) inhibition of mitochondrial substrate utilization is associated with increased insulinstimulated
glucose uptake; 2) stimulation of mitochondrial biogenesis is related to increased energy expenditure
and potentially weight loss. The mode-of-action of both mechanistic hypotheses is currently
unknown and potentially controversial since they contradict other experimental findings. However, the
fact that both processes are stimulated by different types of compounds with different sites of action
supports their potential existence.
Conclusion: This review summarizes the data that support these two hypotheses; with the hope that this
will stimulate further research and intensify the development of future drugs for the treatment of obesity
and type-2 diabetes.
Keywords: Obesity, type 2 diabetes, mitochondria, biogenesis, inhibiting substrate uptake.
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