The Polycomb protein, Bmi1, regulates insulin sensitivity

Abstract

ObjectiveThe Polycomb Repressive Complexes (PRC) 1 and 2 function to epigenetically repress target genes. The PRC1 component, Bmi1, plays a crucial role in maintenance of glucose homeostasis and beta cell mass through repression of the Ink4a/Arf locus. Here we have explored the role of Bmi1 in regulating glucose homeostasis in the adult animal, which had not been previously reported due to poor postnatal survival of Bmi1−/− mice.MethodsThe metabolic phenotype of Bmi1+/− mice was characterized, both in vivo and ex vivo. Glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps were performed. The insulin signaling pathway was assessed at the protein and transcript level.ResultsHere we report a negative correlation between Bmi1 levels and insulin sensitivity in two models of insulin resistance, aging and liver-specific insulin receptor deficiency. Further, heterozygous loss of Bmi1 results in increased insulin sensitivity in adult mice, with no impact on body weight or composition. Hyperinsulinemic-euglycemic clamp reveals increased suppression of hepatic glucose production and increased glucose disposal rate, indicating elevated glucose uptake to peripheral tissues, in Bmi1+/− mice. Enhancement of insulin signaling, specifically an increase in Akt phosphorylation, in liver and, to a lesser extent, in muscle appears to contribute to this phenotype.ConclusionsTogether, these data define a new role for Bmi1 in regulating insulin sensitivity via enhancement of Akt phosphorylation.

Glucose tolerance and insulin sensitivity define adipocyte transcriptional programs in human obesity

“…Interestingly, a consistent, though not significant clustering to Polycomb target genes (Figure 2F right panels and S4B and D – H3K27 me3 ) indicates, in line with recently published findings [12], [13], [14], deregulation of Polycomb domains on chromatin as a common feature of metabolic dysfunction also in human adipocytes.…”

“…Supporting the robustness and sensitivity of our approach, we identified, among the 21 genes with significant MP term associations, two with known function in metabolic control, namely the leptin gene (LEP) [20], [21] and the Polycomb repressive complex 1 subunit BMI1 (B Lymphoma Mo-MLV Insertion Region 1) [14]. Among the remaining 19 genes with significant MP term associations, we focused on the 6 associated with phenotypes related to whole body glucose homeostasis.…”

Insulin resistance and cognitive dysfunction

“…Insulin is a small molecule protein composed of 51 amino acid residues arranged into an A chain of 21 peptides and B chain of 30 peptides that are linked by two disulfides and has a molecular weight of 5808 Da [15]. The metabolic effect of insulin is predominantly regulated by binding to various insulin receptors [16].…”

Long noncoding RNA variations in cardiometabolic diseases

“…115,116 Decreased Bmi1 binding leads to decreased levels of H3K27 trimethylation (H3K27me3) and expression of Enhancer of zeste homolog 2 (Ezh2) that leads to reduced β-cell proliferation in aged mice. [114][115][116][117] Bmi-1 is a member of PRC1 that can repress CDKN2A and is essential for stem cell renewal. 116,117 Importantly, the repression ability of Bmi1 on CDKN2A is dependent on Ezh2 and other components of PRC2.…”

“…[114][115][116][117] Bmi-1 is a member of PRC1 that can repress CDKN2A and is essential for stem cell renewal. 116,117 Importantly, the repression ability of Bmi1 on CDKN2A is dependent on Ezh2 and other components of PRC2. 115,116 CDKN2A expression contributes to aging through limiting the regenerative capacity of β-cells in mice, but still lacks evidence in humans.…”