Blunted refeeding response and increased locomotor activity in mice lacking FoxO1 in synapsin-Cre-expressing neurons

Hongxia Ren, Leona Plum-Morschel, Roger Gutierrez-Juarez, Taylor Y. Lu, Ja Young Kim-Muller, Garrett Heinrich, Sharon L. Wardlaw, Rae Silver, Domenico Accili

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3373-3383
Number of pages11
JournalDiabetes
Volume62
Issue number10
DOIs
StatePublished - Oct 2013
Externally publishedYes

Fingerprint

Synapsins
Locomotion
Leptin
Neurons
Anti-Obesity Agents
Neural Pathways
Pro-Opiomelanocortin
Arcuate Nucleus of Hypothalamus
Suprachiasmatic Nucleus
Feeding Behavior
Energy Metabolism
Genes
Hypothalamus
Homeostasis
Central Nervous System
Eating
Alleles
Body Weight
Hormones
Insulin

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

Ren, H., Plum-Morschel, L., Gutierrez-Juarez, R., Lu, T. Y., Kim-Muller, J. Y., Heinrich, G., ... Accili, D. (2013). Blunted refeeding response and increased locomotor activity in mice lacking FoxO1 in synapsin-Cre-expressing neurons. Diabetes, 62(10), 3373-3383. https://doi.org/10.2337/db13-0597

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.

In: Diabetes, Vol. 62, No. 10, 10.2013, p. 3373-3383.

Research output: Contribution to journalArticle

Ren, H, Plum-Morschel, L, Gutierrez-Juarez, R, Lu, TY, Kim-Muller, JY, Heinrich, G, Wardlaw, SL, Silver, R & Accili, D 2013, 'Blunted refeeding response and increased locomotor activity in mice lacking FoxO1 in synapsin-Cre-expressing neurons', Diabetes, vol. 62, no. 10, pp. 3373-3383. https://doi.org/10.2337/db13-0597
Ren H, Plum-Morschel L, Gutierrez-Juarez R, Lu TY, Kim-Muller JY, Heinrich G et al. Blunted refeeding response and increased locomotor activity in mice lacking FoxO1 in synapsin-Cre-expressing neurons. Diabetes. 2013 Oct;62(10):3373-3383. https://doi.org/10.2337/db13-0597
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. In: Diabetes. 2013 ; Vol. 62, No. 10. pp. 3373-3383.
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