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.

Functional Effects of a Pathogenic Mutation in Cereblon (CRBN) on the Regulation of Protein Synthesis via the AMPK-mTOR Cascade

“…8). These findings not only strengthen the idea that CRBN is an endogenous negative regulator of AMPK (4,5), but also provide a testable hypothesis regarding the mechanism by which the nonsense mutation in CRBN causes mental deficit in humans (Fig. 9).…”

“…In a recent report, we described the generation of Crbn-knock-out (Crbn-KO) mice, in which the Crbn gene is deleted throughout the body (5). To validate the deficiency of Crbn in the brain, we measured levels of the Crbn mRNA by reverse transcription-polymerase chain reaction (RT-PCR) using total RNA extracted from the brains of WT (Crbn ϩ/ϩ), heterozygote KO (Crbn ϩ/Ϫ), and homozygote KO (Crbn Ϫ/Ϫ) mice (Fig.…”

“…In addition, CRBN is the primary target of thalidomide-induced teratogenicity, and is thought to function as a substrate receptor of an E3 ubiquitin ligase complex (3). A recent study showed that CRBN interacts with the ␣ subunit of adenosine monophosphate-activated protein kinase (AMPK) and inhibits the activation of AMPK in vitro as well as in vivo (4,5).…”

Metformin ameliorates diabetic nephropathy in a rat model of low-dose streptozotocin-induced diabetes

“…In a pervious mouse model, high-dose STZ induced direct nephrotoxicity, making it unable to distinguish between the direct toxic effect of STZ and the lesions that resulted from STZ-induced hyperglycemia (20,23,24). In the present study, insulin resistance was induced in a rat model via a high-fat diet (25,26), followed by a single low dose of STZ (30 mg/kg) to induce hyperglycemia for 2 weeks. Elevated glucose levels after 13 weeks successfully induced renal lesions that were similarly present in human patients with DN, hyperglycemia, hyperlipidemia, oxidative stress and renal damage (20).…”

Cereblon in health and disease

“…The energy metabolism-related functions of CRBN have been studied in the whole body of CRBN-deficient mice [43]. CRBN KO mice show constitutively phosphorylated AMPKα and acetyl-CoA carboxylase (ACC), which is a downstream target of AMPK.…”