PMID- 22611086
OWN - NLM
STAT- MEDLINE
DCOM- 20121016
LR  - 20231213
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Print)
IS  - 0892-6638 (Linking)
VI  - 26
IP  - 8
DP  - 2012 Aug
TI  - The clock gene, brain and muscle Arnt-like 1, regulates adipogenesis via Wnt 
      signaling pathway.
PG  - 3453-63
LID - 10.1096/fj.12-205781 [doi]
AB  - Circadian clocks in adipose tissue are known to regulate adipocyte biology. 
      Although circadian dysregulation is associated with development of obesity, the 
      underlying mechanism has not been established. Here we report that disruption of 
      the clock gene, brain and muscle Arnt-like 1 (Bmal1), in mice led to increased 
      adipogenesis, adipocyte hypertrophy, and obesity, compared to wild-type (WT) 
      mice. This is due to its cell-autonomous effect, as Bmal1 deficiency in embryonic 
      fibroblasts, as well as stable shRNA knockdown (KD) in 3T3-L1 preadipocyte and 
      C3H10T1/2 mesenchymal stem cells, promoted adipogenic differentiation. We 
      demonstrate that attenuation of Bmal1 function resulted in down-regulation of 
      genes in the canonical Wnt pathway, known to suppress adipogenesis. Promoters of 
      these genes (Wnt10a, beta-catenin, Dishevelled2, TCF3) displayed Bmal1 occupancy, 
      indicating direct circadian regulation by Bmal1. As a result, Wnt signaling 
      activity was attenuated by Bmal1 KD and augmented by its overexpression. 
      Furthermore, stabilizing beta-catenin through Wnt ligand or GSK-3beta inhibition 
      achieved partial restoration of blunted Wnt activity and suppression of increased 
      adipogenesis induced by Bmal1 KD. Taken together, our study demonstrates that 
      Bmal1 is a critical negative regulator of adipocyte development through 
      transcriptional control of components of the canonical Wnt signaling cascade, and 
      provides a mechanistic link between circadian disruption and obesity.
FAU - Guo, Bingyan
AU  - Guo B
AD  - Center for Diabetes Research, Department of Medicine, The Methodist Hospital 
      Research Institute, Houston, Texas 77030, USA.
FAU - Chatterjee, Somik
AU  - Chatterjee S
FAU - Li, Lifei
AU  - Li L
FAU - Kim, Ji M
AU  - Kim JM
FAU - Lee, Jeongkyung
AU  - Lee J
FAU - Yechoor, Vijay K
AU  - Yechoor VK
FAU - Minze, Laurie J
AU  - Minze LJ
FAU - Hsueh, Willa
AU  - Hsueh W
FAU - Ma, Ke
AU  - Ma K
LA  - eng
GR  - R56 DK089061/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120518
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (ARNTL Transcription Factors)
RN  - 0 (Bmal1 protein, mouse)
SB  - IM
MH  - 3T3-L1 Cells
MH  - ARNTL Transcription Factors/*physiology
MH  - Adipogenesis/*physiology
MH  - Animals
MH  - Cell Differentiation/drug effects
MH  - Circadian Rhythm
MH  - Down-Regulation
MH  - Gene Knockdown Techniques
MH  - Mice
MH  - Obesity/genetics
MH  - Wnt Signaling Pathway/*physiology
PMC - PMC6137895
COIS- The authors thank The Methodist Hospital Research Institute (TMHRI) for funding 
      support and the Center for Diabetes Research for technical assistance.
EDAT- 2012/05/23 06:00
MHDA- 2012/10/17 06:00
PMCR- 2012/08/01
CRDT- 2012/05/22 06:00
PHST- 2012/05/22 06:00 [entrez]
PHST- 2012/05/23 06:00 [pubmed]
PHST- 2012/10/17 06:00 [medline]
PHST- 2012/08/01 00:00 [pmc-release]
AID - fj.12-205781 [pii]
AID - 12-205781 [pii]
AID - 10.1096/fj.12-205781 [doi]
PST - ppublish
SO  - FASEB J. 2012 Aug;26(8):3453-63. doi: 10.1096/fj.12-205781. Epub 2012 May 18.