Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high-fat diet-induced obesity and insulin resistance in mice.
A nonsense mutation in cereblon (CRBN) causes a mild type of mental retardation in humans. An earlier study showed that CRBN negatively regulates the functional activity of AMP-activated protein kinase (AMPK) in vitro by binding directly to the α1-subunit of the AMPK complex. However, the in vivo role of CRBN was not studied. For elucidation of the physiological functions of Crbn, a mouse strain was generated in which the Crbn gene was deleted throughout the whole body. In Crbn-deficient mice fed a normal diet, AMPK in the liver showed hyperphosphorylation, which indicated the constitutive activation of AMPK. Since Crbn-deficient mice showed significantly less weight gain when fed a high-fat diet and their insulin sensitivity was considerably improved, the functions of Crbn in the liver were primarily investigated. These results provide the first in vivo evidence that Crbn is a negative modulator of AMPK, which suggests that Crbn may be a potential target for metabolic disorders of the liver.
School of Life Sciences and Cell Dynamics Research Center and National Leading Research Laboratory for Ion Channels, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea.
Kwang Min
KM
Lee
Seung-Joo
SJ
Yang
Yong Deuk
YD
Kim
Yoo Duk
YD
Choi
Jong Hee
JH
Nam
Cheol Soo
CS
Choi
Hueng-Sik
HS
Choi
Chul-Seung
CS
Park
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000628:therapy; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D044767:Ubiquitin-Protein Ligases; D055372:AMP-Activated Protein Kinases; D010447:Peptide Hydrolases