Summary Dysregulation of O‐GlcNAc modification catalyzed by O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA) contributes to the etiology of chronic diseases of aging, including cancer, cardiovascular disease, type 2 diabetes, and Alzheimer’s disease. Here we found that natural aging in wild‐type mice was marked by a decrease in OGA and OGT protein levels and an increase in O‐GlcNAcylation in various tissues. Genetic disruption of OGA resulted in constitutively elevated O‐GlcNAcylation in embryos and led to neonatal lethality with developmental delay. Importantly, we observed that serum‐stimulated cell cycle entry induced increased O‐GlcNAcylation and decreased its level after release from G2/M arrest, indicating that O‐GlcNAc cycling by OGT and OGA is required for precise cell cycle control. Constitutively, elevated O‐GlcNAcylation by OGA disruption impaired cell proliferation and resulted in mitotic defects with downregulation of mitotic regulators. OGA loss led to mitotic defects including cytokinesis failure and binucleation, increased lagging chromosomes, and micronuclei formation. These findings suggest an important role for O‐GlcNAc cycling by OGA in embryonic development and the regulation of the maintenance of genomic stability linked to the aging process.

Background: PPAR␥ ligands can be used in numerous metabolic syndromes. Results: A novel non-agonist PPAR␥ ligand, UHC1 exhibited great beneficial effects on glucose metabolism and anti-inflammatory response. Conclusion: UHC1 shows anti-diabetic action by blocking CDK5-mediated PPAR␥ phosphorylation. Significance: UHC1 can be a novel therapeutic agent for use in type 2 diabetes and related metabolic disorders.

Blocking phosphorylation of peroxisome proliferator–activated receptor (PPAR)γ at Ser273 is one of the key mechanisms for antidiabetes drugs to target PPARγ. Using high-throughput phosphorylation screening, we here describe that Gleevec blocks cyclin-dependent kinase 5–mediated PPARγ phosphorylation devoid of classical agonism as a PPARγ antagonist ligand. In high fat–fed mice, Gleevec improved insulin sensitivity without causing severe side effects associated with other PPARγ-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 PPARγ phosphorylation. These data illustrate that Gleevec could be a novel therapeutic agent for use in insulin resistance and type 2 diabetes.

Phosphorylation of peroxisome proliferator-activated receptor g (PPARg) at Ser273 by cyclin-dependent kinase 5 (CDK5) in adipose tissue stimulates insulin resistance, but the underlying molecular mechanisms are unclear. We show here that Thrap3 (thyroid hormone receptor-associated protein 3) can directly interact with PPARg when it is phosphorylated at Ser273, and this interaction controls the diabetic gene programming mediated by the phosphorylation of PPARg. Knockdown of Thrap3 restores most of the genes dysregulated by CDK5 action on PPARg in cultured adipocytes. Importantly, reduced expression of Thrap3 in fat tissue by antisense oligonucleotides (ASOs) regulates a specific set of genes, including the key adipokines adiponectin and adipsin, and effectively improves hyperglycemia and insulin resistance in high-fat-fed mice without affecting body weight. These data indicate that Thrap3 plays a crucial role in controlling diabetic gene programming and may provide opportunities for the development of new therapeutics for obesity and type 2 diabetes.