Metformin opposes impaired AMPK and SIRT1 function and deleterious changes in core clock protein expression in white adipose tissue of genetically-obese db/db mice
Article first published online: 27 OCT 2011
© 2011 Blackwell Publishing Ltd
Diabetes, Obesity and Metabolism
Volume 13, Issue 12, pages 1097–1104, December 2011
How to Cite
Caton, P. W., Kieswich, J., Yaqoob, M. M., Holness, M. J. and Sugden, M. C. (2011), Metformin opposes impaired AMPK and SIRT1 function and deleterious changes in core clock protein expression in white adipose tissue of genetically-obese db/db mice. Diabetes, Obesity and Metabolism, 13: 1097–1104. doi: 10.1111/j.1463-1326.2011.01466.x
- Issue published online: 27 OCT 2011
- Article first published online: 27 OCT 2011
- Accepted manuscript online: 6 JUL 2011 12:00AM EST
- Date submitted 7 January 2011; date of first decision 10 February 2011; date of final acceptance 24 June 2011
- AMP-activated protein kinase;
- circadian clock;
- white adipose tissue
Aim: AMPK activates SIRT1 in liver and skeletal muscle. Impaired circadian function is associated with development of obesity. SIRT1 regulates circadian function and is suppressed in white adipose tissue (WAT) of obese patients. We examined the potential role of AMPK and SIRT1 in regulation of circadian components in WAT of obese db/db mice and in mice fed a high-fat diet (HFD), and investigated whether metformin-mediated activation of AMPK opposed any deleterious changes in the WAT clock mechanism.
Methods:db/+ and db/db mice were administered metformin (250 mg/kg/day; 7 days). Separately, mice were fed HFD for 16-weeks. 3T3-L1 adipocytes were incubated with metformin, EX527 or FK866, inhibitors of SIRT1 and NAMPT, respectively. Gene and protein expression were measured by qRT-PCR and immunoblotting.
Results: AMPK activity, NAMPT expression and SIRT1 expression were decreased in WAT of db/db and HFD mice, in association with suppressed expression of the core circadian components CLOCK and BMAL1. Expression of Pparγ and the adipogenic repressors Irf3 and Irf4 were also suppressed. Metformin increased AMPK activity in WAT of db/db mice and in metformin-treated adipocytes, with increased NAMPT, SIRT1 and circadian component expression. Metformin-mediated induction of Clock mRNA in adipocytes was blocked by inhibition of NAMPT and SIRT1.
Conclusions: Decreased AMPK-SIRT1 signalling in db/db and HFD mice impacts WAT circadian function causing dysregulated lipid regulation, favouring an obese phenotype. Metformin mediates a phenotypic shift away from lipid accretion through AMPK-NAMPT-SIRT1 mediated changes in clock components, supporting chronotherapeutic treatment approaches for obesity.