Tag Archives: Promotes

DDB1-Mediated CRY1 Degradation Promotes FOXO1-Driven Gluconeogenesis in Liver

Targeted protein degradation through ubiquitination is an important step in the regulation of glucose metabolism. Here, we present evidence that the DDB1-CUL4A ubiquitin E3 ligase functions as a novel metabolic regulator that promotes FOXO1-driven hepatic gluconeogenesis. In vivo, hepatocyte-specific Ddb1 deletion leads to impaired hepatic gluconeogenesis in the mouse liver but protects mice from high-fat diet–induced hyperglycemia. Lack of Ddb1 downregulates FOXO1 protein expression and impairs FOXO1-driven gluconeogenic response. Mechanistically, we discovered that DDB1 enhances FOXO1 protein stability via degrading the circadian protein cryptochrome 1 (CRY1), a known target of DDB1 E3 ligase. In the Cry1 depletion condition, insulin fails to reduce the nuclear FOXO1 abundance and suppress gluconeogenic gene expression. Chronic depletion of Cry1 in the mouse liver not only increases FOXO1 protein but also enhances hepatic gluconeogenesis. Thus, we have identified the DDB1-mediated CRY1 degradation as an important target of insulin action on glucose homeostasis.

Diabetes Journal current issue





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Lack of CUL4B in Adipocytes Promotes PPAR{gamma}-Mediated Adipose Tissue Expansion and Insulin Sensitivity

Obesity and obesity-associated diseases are linked to dysregulation of the peroxisome proliferator–activated receptor (PPAR) signaling pathway. Identification of the factors that regulate PPAR expression and activity is crucial for combating obesity. However, the ubiquitin E3 ligases that target PPAR for proteasomal degradation have been rarely identified, and their functions in vivo have not been characterized. Here we report that CUL4B-RING E3 ligase (CRL4B) negatively regulates PPAR by promoting its polyubiquitination and proteasomal degradation. Depletion of CUL4B led to upregulation of PPAR-regulated genes and facilitated adipogenesis. Adipocyte-specific Cul4b knockout (AKO) mice being fed a high-fat diet exhibited increased body fat accumulation that was mediated by increased adipogenesis. However, AKO mice showed improved metabolic phenotypes, including increased insulin sensitivity and glucose tolerance. Correspondingly, there was a decreased inflammatory response in adipose tissues of AKO mice. Genetic inhibition of CUL4B thus appears to phenocopy the beneficial effects of PPAR agonists. Collectively, this study establishes a critical role of CRL4B in the regulation of PPAR stability and insulin sensitivity and suggests that CUL4B could be a potential therapeutic target for combating obesity and metabolic syndromes.

Diabetes Journal current issue





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O-GlcNAcylation of Orphan Nuclear Receptor Estrogen-Related Receptor {gamma} Promotes Hepatic Gluconeogenesis

Estrogen-related receptor (ERR) is a major positive regulator of hepatic gluconeogenesis. Its transcriptional activity is suppressed by phosphorylation signaled by insulin in the fed state, but whether posttranslational modification alters its gluconeogenic activity in the fasted state is not known. Metabolically active hepatocytes direct a small amount of glucose into the hexosamine biosynthetic pathway, leading to protein OGlcNAcylation. In this study, we demonstrate that ERR is O-GlcNAcylated by O-GlcNAc transferase in the fasted state. This stabilizes the protein by inhibiting proteasome-mediated protein degradation, increasing ERR recruitment to gluconeogenic gene promoters. Mass spectrometry identifies two serine residues (S317, S319) present in the ERR ligand-binding domain that are O-GlcNAcylated. Mutation of these residues destabilizes ERR protein and blocks the ability of ERR to induce gluconeogenesis in vivo. The impact of this pathway on gluconeogenesis in vivo was confirmed by the observation that decreasing the amount of O-GlcNAcylated ERR by overexpressing the deglycosylating enzyme O-GlcNAcase decreases ERR-dependent glucose production in fasted mice. We conclude that O-GlcNAcylation of ERR serves as a major signal to promote hepatic gluconeogenesis.

Diabetes Journal current issue





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PPAR{gamma} Antagonist Gleevec Improves Insulin Sensitivity and Promotes the Browning of White Adipose Tissue

Blocking phosphorylation of peroxisome proliferator–activated receptor (PPAR) at Ser273 is one of the key mechanisms for antidiabetes drugs to target PPAR. Using high-throughput phosphorylation screening, we here describe that Gleevec blocks cyclin-dependent kinase 5–mediated PPAR phosphorylation devoid of classical agonism as a PPAR antagonist ligand. In high fat–fed mice, Gleevec improved insulin sensitivity without causing severe side effects associated with other PPAR-targeting drugs. Furthermore, Gleevec reduces lipogenic and gluconeogenic gene expression in liver and ameliorates inflammation in adipose tissues. Interestingly, Gleevec increases browning of white adipose tissue and energy expenditure. Taken together, the results indicate that Gleevec exhibits greater beneficial effects on both glucose/lipid metabolism and energy homeostasis by blocking PPAR phosphorylation. These data illustrate that Gleevec could be a novel therapeutic agent for use in insulin resistance and type 2 diabetes.

Diabetes Journal current issue





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