Targeting PGC-1α to control energy homeostasis

Abstract

The prevalence of Type 2 diabetes is increasing at an alarming rate in most parts of the world. Effective therapeutic drugs are urgently needed, not only to control the disease but also to prevent or delay its progression. Therapies that target the underlying pathogenesis could, in theory, hold such potential. Recent evidence strongly suggests that impaired mitochondrial function is part of the underlying pathogenesis of insulin resistance and Type 2 diabetes. Peroxisome proliferator-activated receptor γ co-activator-1 α (PGC-1α) is a transcription co-activator that plays a key role in regulating mitochondrial biogenesis and energy metabolism in multiple tissues. Thus, improvement and restoration of mitochondrial function and oxidative capacity through activation of PGC-1α could provide new treatments for metabolic diseases. A diverse array of proteins has been shown to regulate PGC-1α transcription and/or activity, some of which represent promising targets for pharmaceutical intervention.

Keywords::

• estrogen-related receptor α
• insulin resistance
• mitochondrial biogenesis
• oxidative phosphorylation
• peroxisome proliferator-activated receptor γ
• co-activator-1 α
• Type 2 diabetes
• sirtuin 1

Acknowledgements

The authors are grateful to J Smith (Sirtris Pharmaceuticals, Inc.), SC Stevenson, T Hughes (Novartis Institutes for BioMedical Research, Inc.) and Y-S Tzeng (Boston University) for helpful comments on the manuscript.

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