Limits...
The cAMP-HMGA1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis.

Chiefari E, Paonessa F, Iiritano S, Le Pera I, Palmieri D, Brunetti G, Lupo A, Colantuoni V, Foti D, Gulletta E, De Sarro G, Fusco A, Brunetti A - BMC Biol. (2009)

Bottom Line: These results indicate that HMGA1 is an important modulator of RBP4 gene expression in vivo.Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans.Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Catanzaro, Italy. echiefari@libero.it

ABSTRACT

Background: We previously showed that mice lacking the high mobility group A1 gene (Hmga1-knockout mice) developed a type 2-like diabetic phenotype, in which cell-surface insulin receptors were dramatically reduced (below 10% of those in the controls) in the major targets of insulin action, and glucose intolerance was associated with increased peripheral insulin sensitivity. This particular phenotype supports the existence of compensatory mechanisms of insulin resistance that promote glucose uptake and disposal in peripheral tissues by either insulin-dependent or insulin-independent mechanisms. We explored the role of these mechanisms in the regulation of glucose homeostasis by studying the Hmga1-knockout mouse model. Also, the hypothesis that increased insulin sensitivity in Hmga1-deficient mice could be related to the deficit of an insulin resistance factor is discussed.

Results: We first show that HMGA1 is needed for basal and cAMP-induced retinol-binding protein 4 (RBP4) gene and protein expression in living cells of both human and mouse origin. Then, by employing the Hmga1-knockout mouse model, we provide evidence for the identification of a novel biochemical pathway involving HMGA1 and the RBP4, whose activation by the cAMP-signaling pathway may play an essential role for maintaining glucose metabolism homeostasis in vivo, in certain adverse metabolic conditions in which insulin action is precluded. In comparative studies of normal and mutant mice, glucagon administration caused a considerable upregulation of HMGA1 and RBP4 expression both at the mRNA and protein level in wild-type animals. Conversely, in Hmga1-knockout mice, basal and glucagon-mediated expression of RBP4 was severely attenuated and correlated inversely with increased Glut4 mRNA and protein abundance in skeletal muscle and fat, in which the activation state of the protein kinase Akt, an important downstream mediator of the metabolic effects of insulin on Glut4 translocation and carbohydrate metabolism, was simultaneously increased.

Conclusion: These results indicate that HMGA1 is an important modulator of RBP4 gene expression in vivo. Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans. Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.

Show MeSH

Related in: MedlinePlus

Effects of recombinant RBP4 administration on Akt phosphorylation and Glut4 protein expression in Hmga1-deficient mice. Basal (saline) levels of pAkt (left) and Glut4 (right) were increased in skeletal muscle of saline-injected Hmga1-deficient mice compared with controls, and were reduced following RBP4-injection (n = 6 per genotype). Densitometric quantifications of three independent experiments from 3 animals per genotype are shown, together with representative Western blots of pAkt, Glut4, and serum RBP4 of saline and RBP4-injected mice. *P < 0.05 versus Hmga1+/+.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2698822&req=5

Figure 8: Effects of recombinant RBP4 administration on Akt phosphorylation and Glut4 protein expression in Hmga1-deficient mice. Basal (saline) levels of pAkt (left) and Glut4 (right) were increased in skeletal muscle of saline-injected Hmga1-deficient mice compared with controls, and were reduced following RBP4-injection (n = 6 per genotype). Densitometric quantifications of three independent experiments from 3 animals per genotype are shown, together with representative Western blots of pAkt, Glut4, and serum RBP4 of saline and RBP4-injected mice. *P < 0.05 versus Hmga1+/+.

Mentions: To demonstrate that increased insulin sensitivity in mutant mice was directly due to HMGA1 regulation of RBP4, we determined the effect of recombinant RBP4 administration on Akt phosphorylation and Glut4 protein expression in skeletal muscle from Hmga1-deficient mice. As shown in Figure 8, Akt phosphorylation was reduced in muscle from RBP4-injected mutant animals compared with saline-injected Hmga1 mutants. The reduction in Akt phosphorylation in these genotypes correlated inversely with RBP4 serum levels in the same animals (Figure 8) and paralleled the reduction of Glut4 in skeletal muscle and adipose (not shown) plasma membranes (Figure 8), indicating that, in these conditions, activation of the Akt-Glut4 pathway is regulated, at least in part, by circulating RBP4. Plasma insulin levels were slightly higher in RBP4-injected mice, but no significant difference was found (1.6 ± 0.2 and 1.2 ± 0.2 in RBP4-injected Hmga1+/- and Hmga1-/- respectively, versus 1.4 ± 0.1 and 0.9 ± 0.1 ng/ml in saline-injected Hmga1+/- and Hmga1-/- mice).


The cAMP-HMGA1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis.

Chiefari E, Paonessa F, Iiritano S, Le Pera I, Palmieri D, Brunetti G, Lupo A, Colantuoni V, Foti D, Gulletta E, De Sarro G, Fusco A, Brunetti A - BMC Biol. (2009)

Effects of recombinant RBP4 administration on Akt phosphorylation and Glut4 protein expression in Hmga1-deficient mice. Basal (saline) levels of pAkt (left) and Glut4 (right) were increased in skeletal muscle of saline-injected Hmga1-deficient mice compared with controls, and were reduced following RBP4-injection (n = 6 per genotype). Densitometric quantifications of three independent experiments from 3 animals per genotype are shown, together with representative Western blots of pAkt, Glut4, and serum RBP4 of saline and RBP4-injected mice. *P < 0.05 versus Hmga1+/+.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2698822&req=5

Figure 8: Effects of recombinant RBP4 administration on Akt phosphorylation and Glut4 protein expression in Hmga1-deficient mice. Basal (saline) levels of pAkt (left) and Glut4 (right) were increased in skeletal muscle of saline-injected Hmga1-deficient mice compared with controls, and were reduced following RBP4-injection (n = 6 per genotype). Densitometric quantifications of three independent experiments from 3 animals per genotype are shown, together with representative Western blots of pAkt, Glut4, and serum RBP4 of saline and RBP4-injected mice. *P < 0.05 versus Hmga1+/+.
Mentions: To demonstrate that increased insulin sensitivity in mutant mice was directly due to HMGA1 regulation of RBP4, we determined the effect of recombinant RBP4 administration on Akt phosphorylation and Glut4 protein expression in skeletal muscle from Hmga1-deficient mice. As shown in Figure 8, Akt phosphorylation was reduced in muscle from RBP4-injected mutant animals compared with saline-injected Hmga1 mutants. The reduction in Akt phosphorylation in these genotypes correlated inversely with RBP4 serum levels in the same animals (Figure 8) and paralleled the reduction of Glut4 in skeletal muscle and adipose (not shown) plasma membranes (Figure 8), indicating that, in these conditions, activation of the Akt-Glut4 pathway is regulated, at least in part, by circulating RBP4. Plasma insulin levels were slightly higher in RBP4-injected mice, but no significant difference was found (1.6 ± 0.2 and 1.2 ± 0.2 in RBP4-injected Hmga1+/- and Hmga1-/- respectively, versus 1.4 ± 0.1 and 0.9 ± 0.1 ng/ml in saline-injected Hmga1+/- and Hmga1-/- mice).

Bottom Line: These results indicate that HMGA1 is an important modulator of RBP4 gene expression in vivo.Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans.Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Catanzaro, Italy. echiefari@libero.it

ABSTRACT

Background: We previously showed that mice lacking the high mobility group A1 gene (Hmga1-knockout mice) developed a type 2-like diabetic phenotype, in which cell-surface insulin receptors were dramatically reduced (below 10% of those in the controls) in the major targets of insulin action, and glucose intolerance was associated with increased peripheral insulin sensitivity. This particular phenotype supports the existence of compensatory mechanisms of insulin resistance that promote glucose uptake and disposal in peripheral tissues by either insulin-dependent or insulin-independent mechanisms. We explored the role of these mechanisms in the regulation of glucose homeostasis by studying the Hmga1-knockout mouse model. Also, the hypothesis that increased insulin sensitivity in Hmga1-deficient mice could be related to the deficit of an insulin resistance factor is discussed.

Results: We first show that HMGA1 is needed for basal and cAMP-induced retinol-binding protein 4 (RBP4) gene and protein expression in living cells of both human and mouse origin. Then, by employing the Hmga1-knockout mouse model, we provide evidence for the identification of a novel biochemical pathway involving HMGA1 and the RBP4, whose activation by the cAMP-signaling pathway may play an essential role for maintaining glucose metabolism homeostasis in vivo, in certain adverse metabolic conditions in which insulin action is precluded. In comparative studies of normal and mutant mice, glucagon administration caused a considerable upregulation of HMGA1 and RBP4 expression both at the mRNA and protein level in wild-type animals. Conversely, in Hmga1-knockout mice, basal and glucagon-mediated expression of RBP4 was severely attenuated and correlated inversely with increased Glut4 mRNA and protein abundance in skeletal muscle and fat, in which the activation state of the protein kinase Akt, an important downstream mediator of the metabolic effects of insulin on Glut4 translocation and carbohydrate metabolism, was simultaneously increased.

Conclusion: These results indicate that HMGA1 is an important modulator of RBP4 gene expression in vivo. Further, they provide evidence for the identification of a novel biochemical pathway involving the cAMP-HMGA1-RBP4 system, whose activation may play a role in glucose homeostasis in both rodents and humans. Elucidating these mechanisms has importance for both fundamental biology and therapeutic implications.

Show MeSH
Related in: MedlinePlus