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The Polycomb protein, Bmi1, regulates insulin sensitivity.

Cannon CE, Titchenell PM, Groff DN, El Ouaamari A, Kulkarni RN, Birnbaum MJ, Stoffers DA - Mol Metab (2014)

Bottom Line: The 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.Glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps were performed.

View Article: PubMed Central - PubMed

Affiliation: Institute for Diabetes, Obesity and Metabolism and the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.

ABSTRACT

Objective: The 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.

Methods: The 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.

Results: Here 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.

Conclusions: Together, these data define a new role for Bmi1 in regulating insulin sensitivity via enhancement of Akt phosphorylation.

No MeSH data available.


Related in: MedlinePlus

Bmi1+/− mice are partially protected from high fat diet-induced insulin resistance and require less insulin to maintain glucose homeostasis. (A) Western blots of lysates from Bmi1+/+ and Bmi1+/− male liver lysates showing levels of Bmi1 protein. Quantification of western blots from 5 animals per genotype. (B–C) Glucose and insulin tolerance tests of 16–18 week old LFD and HFD-fed Bmi1+/+ and Bmi1+/− males (B) 1 g/kg IP glucose bolus, p= 0.1211 by two-way ANOVA for HFD Bmi1+/+ vs HFD Bmi1+/− and (C) 1.5 U/kg IP insulin, p = 0.0095 by two-way ANOVA for HFD Bmi1+/+ vs HFD Bmi1+/−. (D) Body weights of LFD and HFD-fed Bmi1+/+ and Bmi1+/− males. (E) Lean and fat mass unaffected in HFD Bmi1+/+ and Bmi1+/− mice at 29 weeks of age, as measured by NMR. n = 7–8 mice per genotype for all assessments. *p < 0.05 **p < 0.01 vs Bmi1+/+ (F) Plasma insulin at 0 and 3 min after 2 g/kg IP glucose bolus. *p < 0.05; n = 13–15 per genotype.
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fig2: Bmi1+/− mice are partially protected from high fat diet-induced insulin resistance and require less insulin to maintain glucose homeostasis. (A) Western blots of lysates from Bmi1+/+ and Bmi1+/− male liver lysates showing levels of Bmi1 protein. Quantification of western blots from 5 animals per genotype. (B–C) Glucose and insulin tolerance tests of 16–18 week old LFD and HFD-fed Bmi1+/+ and Bmi1+/− males (B) 1 g/kg IP glucose bolus, p= 0.1211 by two-way ANOVA for HFD Bmi1+/+ vs HFD Bmi1+/− and (C) 1.5 U/kg IP insulin, p = 0.0095 by two-way ANOVA for HFD Bmi1+/+ vs HFD Bmi1+/−. (D) Body weights of LFD and HFD-fed Bmi1+/+ and Bmi1+/− males. (E) Lean and fat mass unaffected in HFD Bmi1+/+ and Bmi1+/− mice at 29 weeks of age, as measured by NMR. n = 7–8 mice per genotype for all assessments. *p < 0.05 **p < 0.01 vs Bmi1+/+ (F) Plasma insulin at 0 and 3 min after 2 g/kg IP glucose bolus. *p < 0.05; n = 13–15 per genotype.

Mentions: To assess the potential role of Bmi1 in insulin sensitivity, we characterized glucose homeostasis of Bmi1-deficient mice. In order to exacerbate what we predicted might be a mild phenotype, Bmi1+/− males and Bmi1+/+ littermates were placed on a high fat diet at weaning and followed through 18 weeks of age. Bmi1 heterozygosity resulted in an approximate 60% reduction in Bmi1 protein (Figure 2A). High fat diet induced an equivalent degree of weight gain in both genotypes (Figure 2D). Surprisingly, glucose tolerance was not worse in Bmi1+/− mice, rather there was a trend toward improved glucose tolerance (Figure 2B; p = 0.12 by two-way ANOVA for HFD-fed Bmi1+/+ vs HFD-fed Bmi1+/−). Insulin tolerance testing (ITT) revealed that Bmi1 heterozygosity confers partial protection from high fat diet-induced insulin resistance (Figure 2C; p = 0.0095 by two-way ANOVA for HFD-fed Bmi1+/+ vs HFD-fed Bmi1+/−). Bmi1 animals have multiple phenotypes resulting from severe deficiencies in cell replication, including stunted growth [8]. In contrast, body weight and composition were indistinguishable between Bmi1+/+ and Bmi1+/− littermates (Figure 2D–E). These observations indicate that the role of Bmi1 in whole-body insulin sensitivity is independent of body weight or adiposity.


The Polycomb protein, Bmi1, regulates insulin sensitivity.

Cannon CE, Titchenell PM, Groff DN, El Ouaamari A, Kulkarni RN, Birnbaum MJ, Stoffers DA - Mol Metab (2014)

Bmi1+/− mice are partially protected from high fat diet-induced insulin resistance and require less insulin to maintain glucose homeostasis. (A) Western blots of lysates from Bmi1+/+ and Bmi1+/− male liver lysates showing levels of Bmi1 protein. Quantification of western blots from 5 animals per genotype. (B–C) Glucose and insulin tolerance tests of 16–18 week old LFD and HFD-fed Bmi1+/+ and Bmi1+/− males (B) 1 g/kg IP glucose bolus, p= 0.1211 by two-way ANOVA for HFD Bmi1+/+ vs HFD Bmi1+/− and (C) 1.5 U/kg IP insulin, p = 0.0095 by two-way ANOVA for HFD Bmi1+/+ vs HFD Bmi1+/−. (D) Body weights of LFD and HFD-fed Bmi1+/+ and Bmi1+/− males. (E) Lean and fat mass unaffected in HFD Bmi1+/+ and Bmi1+/− mice at 29 weeks of age, as measured by NMR. n = 7–8 mice per genotype for all assessments. *p < 0.05 **p < 0.01 vs Bmi1+/+ (F) Plasma insulin at 0 and 3 min after 2 g/kg IP glucose bolus. *p < 0.05; n = 13–15 per genotype.
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fig2: Bmi1+/− mice are partially protected from high fat diet-induced insulin resistance and require less insulin to maintain glucose homeostasis. (A) Western blots of lysates from Bmi1+/+ and Bmi1+/− male liver lysates showing levels of Bmi1 protein. Quantification of western blots from 5 animals per genotype. (B–C) Glucose and insulin tolerance tests of 16–18 week old LFD and HFD-fed Bmi1+/+ and Bmi1+/− males (B) 1 g/kg IP glucose bolus, p= 0.1211 by two-way ANOVA for HFD Bmi1+/+ vs HFD Bmi1+/− and (C) 1.5 U/kg IP insulin, p = 0.0095 by two-way ANOVA for HFD Bmi1+/+ vs HFD Bmi1+/−. (D) Body weights of LFD and HFD-fed Bmi1+/+ and Bmi1+/− males. (E) Lean and fat mass unaffected in HFD Bmi1+/+ and Bmi1+/− mice at 29 weeks of age, as measured by NMR. n = 7–8 mice per genotype for all assessments. *p < 0.05 **p < 0.01 vs Bmi1+/+ (F) Plasma insulin at 0 and 3 min after 2 g/kg IP glucose bolus. *p < 0.05; n = 13–15 per genotype.
Mentions: To assess the potential role of Bmi1 in insulin sensitivity, we characterized glucose homeostasis of Bmi1-deficient mice. In order to exacerbate what we predicted might be a mild phenotype, Bmi1+/− males and Bmi1+/+ littermates were placed on a high fat diet at weaning and followed through 18 weeks of age. Bmi1 heterozygosity resulted in an approximate 60% reduction in Bmi1 protein (Figure 2A). High fat diet induced an equivalent degree of weight gain in both genotypes (Figure 2D). Surprisingly, glucose tolerance was not worse in Bmi1+/− mice, rather there was a trend toward improved glucose tolerance (Figure 2B; p = 0.12 by two-way ANOVA for HFD-fed Bmi1+/+ vs HFD-fed Bmi1+/−). Insulin tolerance testing (ITT) revealed that Bmi1 heterozygosity confers partial protection from high fat diet-induced insulin resistance (Figure 2C; p = 0.0095 by two-way ANOVA for HFD-fed Bmi1+/+ vs HFD-fed Bmi1+/−). Bmi1 animals have multiple phenotypes resulting from severe deficiencies in cell replication, including stunted growth [8]. In contrast, body weight and composition were indistinguishable between Bmi1+/+ and Bmi1+/− littermates (Figure 2D–E). These observations indicate that the role of Bmi1 in whole-body insulin sensitivity is independent of body weight or adiposity.

Bottom Line: The 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.Glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps were performed.

View Article: PubMed Central - PubMed

Affiliation: Institute for Diabetes, Obesity and Metabolism and the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.

ABSTRACT

Objective: The 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.

Methods: The 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.

Results: Here 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.

Conclusions: Together, these data define a new role for Bmi1 in regulating insulin sensitivity via enhancement of Akt phosphorylation.

No MeSH data available.


Related in: MedlinePlus