Blunted Refeeding Response and Increased Locomotor Activity in Mice Lacking FoxO1 in Synapsin-Cre–Expressing Neurons

Successful development of antiobesity agents requires detailed knowledge of neural pathways controlling body weight, eating behavior, and peripheral metabolism. Genetic ablation of FoxO1 in selected hypothalamic neurons decreases food intake, increases energy expenditure, and improves glucose homeos...

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Main Authors:	Ren, Hongxia, Plum-Morschel, Leona, Gutierrez-Juarez, Roger, Lu, Taylor Y., Kim-Muller, Ja Young, Heinrich, Garrett, Wardlaw, Sharon L., Silver, Rae, Accili, Domenico
Format:	Online
Language:	English
Published:	American Diabetes Association 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781468/

id	pubmed-3781468
recordtype	oai_dc
spelling	pubmed-37814682014-10-01 Blunted Refeeding Response and Increased Locomotor Activity in Mice Lacking FoxO1 in Synapsin-Cre–Expressing Neurons Ren, Hongxia Plum-Morschel, Leona Gutierrez-Juarez, Roger Lu, Taylor Y. Kim-Muller, Ja Young Heinrich, Garrett Wardlaw, Sharon L. Silver, Rae Accili, Domenico Original Research Successful development of antiobesity agents requires detailed knowledge of neural pathways controlling body weight, eating behavior, and peripheral metabolism. Genetic ablation of FoxO1 in selected hypothalamic neurons decreases food intake, increases energy expenditure, and improves glucose homeostasis, highlighting the role of this gene in insulin and leptin signaling. However, little is known about potential effects of FoxO1 in other neurons. To address this question, we executed a broad-based neuronal ablation of FoxO1 using Synapsin promoter–driven Cre to delete floxed Foxo1 alleles. Lineage-tracing experiments showed that NPY/AgRP and POMC neurons were minimally affected by the knockout. Nonetheless, Syn-Cre-Foxo1 knockouts demonstrated a catabolic energy homeostatic phenotype with a blunted refeeding response, increased sensitivity to leptin and amino acid signaling, and increased locomotor activity, likely attributable to increased melanocortinergic tone. We confirmed these data in mice lacking the three Foxo genes. The effects on locomotor activity could be reversed by direct delivery of constitutively active FoxO1 to the mediobasal hypothalamus, but not to the suprachiasmatic nucleus. The data reveal that the integrative function of FoxO1 extends beyond the arcuate nucleus, suggesting that central nervous system inhibition of FoxO1 function can be leveraged to promote hormone sensitivity and prevent a positive energy balance. American Diabetes Association 2013-10 2013-09-17 /pmc/articles/PMC3781468/ /pubmed/23835335 http://dx.doi.org/10.2337/db13-0597 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Ren, Hongxia Plum-Morschel, Leona Gutierrez-Juarez, Roger Lu, Taylor Y. Kim-Muller, Ja Young Heinrich, Garrett Wardlaw, Sharon L. Silver, Rae Accili, Domenico
spellingShingle	Ren, Hongxia Plum-Morschel, Leona Gutierrez-Juarez, Roger Lu, Taylor Y. Kim-Muller, Ja Young Heinrich, Garrett Wardlaw, Sharon L. Silver, Rae Accili, Domenico Blunted Refeeding Response and Increased Locomotor Activity in Mice Lacking FoxO1 in Synapsin-Cre–Expressing Neurons
author_facet	Ren, Hongxia Plum-Morschel, Leona Gutierrez-Juarez, Roger Lu, Taylor Y. Kim-Muller, Ja Young Heinrich, Garrett Wardlaw, Sharon L. Silver, Rae Accili, Domenico
author_sort	Ren, Hongxia
title	Blunted Refeeding Response and Increased Locomotor Activity in Mice Lacking FoxO1 in Synapsin-Cre–Expressing Neurons
title_short	Blunted Refeeding Response and Increased Locomotor Activity in Mice Lacking FoxO1 in Synapsin-Cre–Expressing Neurons
title_full	Blunted Refeeding Response and Increased Locomotor Activity in Mice Lacking FoxO1 in Synapsin-Cre–Expressing Neurons
title_fullStr	Blunted Refeeding Response and Increased Locomotor Activity in Mice Lacking FoxO1 in Synapsin-Cre–Expressing Neurons
title_full_unstemmed	Blunted Refeeding Response and Increased Locomotor Activity in Mice Lacking FoxO1 in Synapsin-Cre–Expressing Neurons
title_sort	blunted refeeding response and increased locomotor activity in mice lacking foxo1 in synapsin-cre–expressing neurons
description	Successful development of antiobesity agents requires detailed knowledge of neural pathways controlling body weight, eating behavior, and peripheral metabolism. Genetic ablation of FoxO1 in selected hypothalamic neurons decreases food intake, increases energy expenditure, and improves glucose homeostasis, highlighting the role of this gene in insulin and leptin signaling. However, little is known about potential effects of FoxO1 in other neurons. To address this question, we executed a broad-based neuronal ablation of FoxO1 using Synapsin promoter–driven Cre to delete floxed Foxo1 alleles. Lineage-tracing experiments showed that NPY/AgRP and POMC neurons were minimally affected by the knockout. Nonetheless, Syn-Cre-Foxo1 knockouts demonstrated a catabolic energy homeostatic phenotype with a blunted refeeding response, increased sensitivity to leptin and amino acid signaling, and increased locomotor activity, likely attributable to increased melanocortinergic tone. We confirmed these data in mice lacking the three Foxo genes. The effects on locomotor activity could be reversed by direct delivery of constitutively active FoxO1 to the mediobasal hypothalamus, but not to the suprachiasmatic nucleus. The data reveal that the integrative function of FoxO1 extends beyond the arcuate nucleus, suggesting that central nervous system inhibition of FoxO1 function can be leveraged to promote hormone sensitivity and prevent a positive energy balance.
publisher	American Diabetes Association
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781468/
_version_	1612013769928474624

Blunted Refeeding Response and Increased Locomotor Activity in Mice Lacking FoxO1 in Synapsin-Cre–Expressing Neurons

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