Research Paper Volume 12, Issue 19 pp 18942—18956
Activation of LKB1 rescues 3T3-L1 adipocytes from senescence induced by Sirt1 knock-down: a pivotal role of LKB1 in cellular aging
- 1 The Department of Endocrinology, The First People’s Hospital in Chongqing Liangjiang New Area, Chongqing, China
- 2 The Department of Laboratory Medicine, The Thirteenth People's Hospital of Chongqing, Chongqing, China
- 3 The Department of Endocrinology, The First People’s Hospital in Chongqing Liangjiang New Area, Chongqing, China
- 4 ALPCO Diagnostics, Salem, NH 03079, USA
- 5 Bonumose LLC, Charlottesville, VA 22911, USA
- 6 Boston University School of Medicine, Boston, MA 02118, USA
- 7 Department of Cardiology, National Defense Medical College, Saitama, Japan
Received: March 14, 2020 Accepted: August 24, 2020 Published: October 10, 2020https://doi.org/10.18632/aging.104052
How to Cite
Copyright: © 2020 Lan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Previous reports have shown that excess calorie intake promotes p53 dependent senescence in mouse adipose tissues. The objective of the current study was to address the mechanism underlying this observation, i.e. adipocyte aging. Using cultured 3T3-L1 cells, we investigated the involvement of energy regulators Sirt1, AMPK, and LKB1 in senescence. Fifteen days post differentiation, Sirt1 knock-down increased senescence-associated beta-galactosidase (SA-β-Gal) staining by 20-40% (p<0.05, n=12) and both cyclin kinase inhibitor p21Cip and chemokine receptor IL8Rb expression by 2-4 fold. ATP and expression of mitochondria Complex 1 were also reduced by 30% and 50%, respectively (p<0.05, n=4). Such energy depletion may have caused the observed increase in AMPK activity, despite LKB1 activity downregulation. This association between Sirt1 and LKB1 activity was confirmed in vivo in mouse adipose tissue. Upregulation of LKB1 activity by expression of the Sirt1-insensitive LKB1-K48R mutant in 3T3-L1 cells completely prevented the senescence-associated changes of Sirt1 knock-down. In addition, cellular senescence, which also occurs in cultured primary human aortic endothelial cells, was largely prevented by ectopic expression of LKB1. These results suggest that LKB1 plays a pivotal role in cellular senescence occurring in adipocytes and other cell types.