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Metformin induces PGC-1α expression and selectively affects hepatic PGC-1α functions
Sanna-Mari Aatsinki1, Marcin Buler, Henriikka Salomäki
1Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.
British Journal of Pharmacology
|January 17, 2014
Summary
Metformin, an AMPK activator, increases hepatic PPARγ coactivator 1α (PGC-1α) expression but selectively suppresses gluconeogenic genes. This selective modulation of PGC-1α functions is a novel mechanism for metformin
Area of Science:
- * Molecular Endocrinology
- * Cellular Metabolism
- * Pharmaceutical Research
Background:
- * Peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1-alpha (PGC-1α) is a key regulator of hepatic gluconeogenesis.
- * Metformin is a widely used antidiabetic drug that activates AMP-activated protein kinase (AMPK).
Purpose of the Study:
- * To investigate the effect of metformin on PGC-1α and its regulated liver functions.
- * To elucidate the role of AMPK in mediating metformin's effects on PGC-1α.
Main Methods:
- * Treatment of mouse and human primary hepatocytes and mice with metformin.
- * Employed adenoviral overexpression, siRNA, and reporter gene constructs for mechanistic studies.
- * Utilized AMPK activators (AICAR) and inhibitors (compound C) to dissect signaling pathways.
Main Results:
- * Metformin increased PGC-1α mRNA and protein in hepatocytes, while AICAR had an opposite effect.
- * Metformin's effect on PGC-1α was dependent on AMPK and sirtuin 1.
- * Metformin down-regulated gluconeogenic genes (PEPCK, G6Pase) and key transcription factors, but not mitochondrial genes regulated by PGC-1α.
Conclusions:
- * Metformin selectively modulates hepatic PGC-1α functions, suppressing gluconeogenesis without affecting mitochondrial gene regulation.
- * Down-regulation of PGC-1α is not required for metformin's suppression of gluconeogenic genes.
- * Selective PGC-1α modulation represents a novel mechanism underlying metformin's therapeutic action in diabetes.
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