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Foxo1 regulates Dbh expression and the activity of the sympathetic nervous system in vivo.

Kajimura D, Paone R, Mann JJ, Karsenty G - Mol Metab (2014)

Bottom Line: Here, we show that FoxO1 is highly expressed in neurons of the locus coeruleus and of various sympathetic ganglions, but not in the adrenal medulla.Consistent with this pattern of expression, mice lacking FoxO1 only in sympathetic neurons (FoxO1 Dbh-/-) display a low sympathetic tone without modification of the catecholamine content in the adrenal medulla.FoxO1 favors catecholamine synthesis because it is a potent regulator of the expression of Dbh that encodes the initial and rate-limiting enzyme in the synthesis of these neurotransmitters.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

ABSTRACT
The transcription factor FoxO1 regulates multiple physiological processes. Here, we show that FoxO1 is highly expressed in neurons of the locus coeruleus and of various sympathetic ganglions, but not in the adrenal medulla. Consistent with this pattern of expression, mice lacking FoxO1 only in sympathetic neurons (FoxO1 Dbh-/-) display a low sympathetic tone without modification of the catecholamine content in the adrenal medulla. As a result, FoxO1 Dbh-/- mice demonstrate an increased insulin secretion, improved glucose tolerance, low energy expenditure, and high bone mass. FoxO1 favors catecholamine synthesis because it is a potent regulator of the expression of Dbh that encodes the initial and rate-limiting enzyme in the synthesis of these neurotransmitters. By identifying FoxO1 as a transcriptional regulator of the sympathetic tone, these results advance our understanding of the control of some aspects of metabolism and of bone mass accrual.

No MeSH data available.


Related in: MedlinePlus

(A) Energy expenditure of 36 week-old FoxO1fl/fl and FoxO1Dbh−/− mice. (B) Food intake of 36 week-old FoxO1fl/fl and FoxO1Dbh−/− mice. (C) Fat pad weight of 36 week-old FoxO1fl/fl and FoxO1Dbh−/− mice. (E and F) Glucose-stimulated insulin secretion test (GSIS), glucose tolerance test (GTT), and insulin tolerance test (ITT) of FoxO1fl/fl and FoxO1Dbh−/− mice.
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fig3: (A) Energy expenditure of 36 week-old FoxO1fl/fl and FoxO1Dbh−/− mice. (B) Food intake of 36 week-old FoxO1fl/fl and FoxO1Dbh−/− mice. (C) Fat pad weight of 36 week-old FoxO1fl/fl and FoxO1Dbh−/− mice. (E and F) Glucose-stimulated insulin secretion test (GSIS), glucose tolerance test (GTT), and insulin tolerance test (ITT) of FoxO1fl/fl and FoxO1Dbh−/− mice.

Mentions: First, we noticed that FoxO1Dbh−/− mice have a significantly lower energy expenditure than control animals as determined by decreased oxygen consumption, carbon dioxide production and heat generation measurements (Figure 3A). In contrast, appetite was normal in FoxO1Dbh−/− mice (Figure 3B). This decrease in energy expenditure in the face of a normal appetite explained, in part, why FoxO1Dbh−/− mice have higher fat pad weights compared with control mice (Figure 3C). Since insulin secretion is regulated by the sympathetic tone [16], we measured insulin secretion and glucose tolerance in FoxO1Dbh−/− and control mice. Glucose-stimulated insulin secretion test showed that insulin secretion was enhanced in FoxO1Dbh−/− compared with FoxO1fl/fl mice (Figure 3D), this is consistent with the decreased activity of the sympathetic nervous system noted in FoxO1Dbh−/− mice. As a result, a glucose tolerance test (GTT) showed that FoxO1Dbh−/− mice exhibited improved glucose tolerance, whereas insulin sensitivity as measured by an insulin tolerance test (ITT) remained normal in FoxO1Dbh−/− mice (Figure 3E,F). These results indicate that FoxO1, through its expression in sympathetic neurons, because it regulates positively the sympathetic tone, affects energy expenditure and insulin secretion.


Foxo1 regulates Dbh expression and the activity of the sympathetic nervous system in vivo.

Kajimura D, Paone R, Mann JJ, Karsenty G - Mol Metab (2014)

(A) Energy expenditure of 36 week-old FoxO1fl/fl and FoxO1Dbh−/− mice. (B) Food intake of 36 week-old FoxO1fl/fl and FoxO1Dbh−/− mice. (C) Fat pad weight of 36 week-old FoxO1fl/fl and FoxO1Dbh−/− mice. (E and F) Glucose-stimulated insulin secretion test (GSIS), glucose tolerance test (GTT), and insulin tolerance test (ITT) of FoxO1fl/fl and FoxO1Dbh−/− mice.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4209360&req=5

fig3: (A) Energy expenditure of 36 week-old FoxO1fl/fl and FoxO1Dbh−/− mice. (B) Food intake of 36 week-old FoxO1fl/fl and FoxO1Dbh−/− mice. (C) Fat pad weight of 36 week-old FoxO1fl/fl and FoxO1Dbh−/− mice. (E and F) Glucose-stimulated insulin secretion test (GSIS), glucose tolerance test (GTT), and insulin tolerance test (ITT) of FoxO1fl/fl and FoxO1Dbh−/− mice.
Mentions: First, we noticed that FoxO1Dbh−/− mice have a significantly lower energy expenditure than control animals as determined by decreased oxygen consumption, carbon dioxide production and heat generation measurements (Figure 3A). In contrast, appetite was normal in FoxO1Dbh−/− mice (Figure 3B). This decrease in energy expenditure in the face of a normal appetite explained, in part, why FoxO1Dbh−/− mice have higher fat pad weights compared with control mice (Figure 3C). Since insulin secretion is regulated by the sympathetic tone [16], we measured insulin secretion and glucose tolerance in FoxO1Dbh−/− and control mice. Glucose-stimulated insulin secretion test showed that insulin secretion was enhanced in FoxO1Dbh−/− compared with FoxO1fl/fl mice (Figure 3D), this is consistent with the decreased activity of the sympathetic nervous system noted in FoxO1Dbh−/− mice. As a result, a glucose tolerance test (GTT) showed that FoxO1Dbh−/− mice exhibited improved glucose tolerance, whereas insulin sensitivity as measured by an insulin tolerance test (ITT) remained normal in FoxO1Dbh−/− mice (Figure 3E,F). These results indicate that FoxO1, through its expression in sympathetic neurons, because it regulates positively the sympathetic tone, affects energy expenditure and insulin secretion.

Bottom Line: Here, we show that FoxO1 is highly expressed in neurons of the locus coeruleus and of various sympathetic ganglions, but not in the adrenal medulla.Consistent with this pattern of expression, mice lacking FoxO1 only in sympathetic neurons (FoxO1 Dbh-/-) display a low sympathetic tone without modification of the catecholamine content in the adrenal medulla.FoxO1 favors catecholamine synthesis because it is a potent regulator of the expression of Dbh that encodes the initial and rate-limiting enzyme in the synthesis of these neurotransmitters.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

ABSTRACT
The transcription factor FoxO1 regulates multiple physiological processes. Here, we show that FoxO1 is highly expressed in neurons of the locus coeruleus and of various sympathetic ganglions, but not in the adrenal medulla. Consistent with this pattern of expression, mice lacking FoxO1 only in sympathetic neurons (FoxO1 Dbh-/-) display a low sympathetic tone without modification of the catecholamine content in the adrenal medulla. As a result, FoxO1 Dbh-/- mice demonstrate an increased insulin secretion, improved glucose tolerance, low energy expenditure, and high bone mass. FoxO1 favors catecholamine synthesis because it is a potent regulator of the expression of Dbh that encodes the initial and rate-limiting enzyme in the synthesis of these neurotransmitters. By identifying FoxO1 as a transcriptional regulator of the sympathetic tone, these results advance our understanding of the control of some aspects of metabolism and of bone mass accrual.

No MeSH data available.


Related in: MedlinePlus