Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature β-cell

Nan Gao, John Le Lay, Wei Qin, Nicolai Doliba, Jonathan Schug, Alan J. Fox, Olga Smirnova, Franz M. Matschinsky, Klaus H. Kaestner

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Foxa1 and Foxa2 play both redundant and distinct roles in early pancreas development. We demonstrate here that inducible ablation of both transcription factors in mature mouse β-cells leads to impaired glucose homeostasis and insulin secretion. The defects in both glucose-stimulated insulin secretion and intracellular calcium oscillation are more pronounced than those in β-cells lacking only Foxa2. Unexpectedly, in contrast to the severe reduction of β-cell-enriched factors contributing to metabolic and secretory pathways, expression of a large number of genes that are involved in neural differentiation and function is significantly elevated. We further demonstrate that expression of carbohydrate response element-binding protein (ChREBP or Mlxipl), an important transcriptional regulator of carbohydrate metabolism, is significantly affected in compound Foxa1/a2 mutant β-cells. ChREBP expression is directly controlled by Foxa1 and Foxa2 in both the fetal endocrine pancreas as well as mature islets. These data demonstrate that Foxa1 and Foxa2 play crucial roles in the development and maintenance of β-cell-specific secretory and metabolic pathways.

Original languageEnglish (US)
Pages (from-to)1594-1604
Number of pages11
JournalMolecular Endocrinology
Volume24
Issue number8
DOIs
StatePublished - Aug 1 2010
Externally publishedYes

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Secretory Pathway
Metabolic Networks and Pathways
Insulin
Glucose
Calcium Signaling
Carbohydrate Metabolism
Response Elements
Islets of Langerhans
Pancreas
Carrier Proteins
Homeostasis
Transcription Factors
Maintenance
Carbohydrates
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

Cite this

Gao, N., Le Lay, J., Qin, W., Doliba, N., Schug, J., Fox, A. J., ... Kaestner, K. H. (2010). Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature β-cell. Molecular Endocrinology, 24(8), 1594-1604. https://doi.org/10.1210/me.2009-0513
Gao, Nan ; Le Lay, John ; Qin, Wei ; Doliba, Nicolai ; Schug, Jonathan ; Fox, Alan J. ; Smirnova, Olga ; Matschinsky, Franz M. ; Kaestner, Klaus H. / Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature β-cell. In: Molecular Endocrinology. 2010 ; Vol. 24, No. 8. pp. 1594-1604.
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Gao, N, Le Lay, J, Qin, W, Doliba, N, Schug, J, Fox, AJ, Smirnova, O, Matschinsky, FM & Kaestner, KH 2010, 'Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature β-cell', Molecular Endocrinology, vol. 24, no. 8, pp. 1594-1604. https://doi.org/10.1210/me.2009-0513

Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature β-cell. / Gao, Nan; Le Lay, John; Qin, Wei; Doliba, Nicolai; Schug, Jonathan; Fox, Alan J.; Smirnova, Olga; Matschinsky, Franz M.; Kaestner, Klaus H.

In: Molecular Endocrinology, Vol. 24, No. 8, 01.08.2010, p. 1594-1604.

Research output: Contribution to journalArticle

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AU - Gao, Nan

AU - Le Lay, John

AU - Qin, Wei

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