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Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high-fat diet-induced obesity and insulin resistance in mice.

Abstract
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.
AuthorsKwang Min Lee, Seung-Joo Yang, Yong Deuk Kim, Yoo Duk Choi, Jong Hee Nam, Cheol Soo Choi, Hueng-Sik Choi, Chul-Seung Park
JournalDiabetes (Diabetes) Vol. 62 Issue 6 Pg. 1855-64 (Jun 2013) ISSN: 1939-327X [Electronic] United States
PMID23349485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Adaptor Proteins, Signal Transducing
  • CRBN protein, human
  • Ubiquitin-Protein Ligases
  • AMP-Activated Protein Kinases
  • Peptide Hydrolases
Topics
  • AMP-Activated Protein Kinases (metabolism)
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Diet, High-Fat (adverse effects)
  • Female
  • Insulin Resistance (genetics, physiology)
  • Liver (enzymology)
  • Male
  • Mice
  • Mice, Knockout
  • Obesity (etiology, genetics, therapy)
  • Peptide Hydrolases (genetics, metabolism)
  • Ubiquitin-Protein Ligases

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