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Updated: May 9, 2026
Assessing Activity-based Anorexia in Mice
Published on: May 14, 2018
Blunted refeeding response and increased locomotor activity in mice lacking FoxO1 in synapsin-Cre-expressing neurons
Hongxia Ren1, Leona Plum-Morschel, Roger Gutierrez-Juarez
1Berrie Diabetes Center, New York, New York.
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.
Insights
Inhibiting FoxO1 in the brain promotes hormone sensitivity and prevents weight gain. This study reveals FoxO1
Area of Science:
- Neuroscience
- Metabolism
- Endocrinology
Background:
- Developing anti-obesity agents requires understanding neural pathways controlling body weight and metabolism.
- FoxO1 (Forkhead box protein O1) plays a role in insulin and leptin signaling, but its function in diverse neuronal populations is unclear.
Purpose of the Study:
- To investigate the effects of broad neuronal ablation of FoxO1 on energy homeostasis.
- To determine if FoxO1 inhibition in the central nervous system can be a therapeutic strategy for metabolic disorders.
Main Methods:
- Utilized Synapsin promoter-driven Cre to achieve broad neuronal deletion of floxed Foxo1 alleles in mice.
- Performed lineage tracing to assess the impact on key hypothalamic nuclei (NPY/AgRP and POMC neurons).
- Administered constitutively active FoxO1 directly to specific brain regions to evaluate rescue effects.
Main Results:
- Neuronal FoxO1 knockout mice exhibited a catabolic phenotype, including reduced feeding, increased energy expenditure, and enhanced sensitivity to leptin and amino acid signaling.
- Increased locomotor activity was observed, linked to elevated melanocortinergic signaling.
- Restoring FoxO1 in the mediobasal hypothalamus, but not the suprachiasmatic nucleus, reversed the effects on activity.
Conclusions:
- FoxO1' s function in regulating energy balance extends beyond the arcuate nucleus.
- Central nervous system inhibition of FoxO1 enhances hormone sensitivity and can prevent positive energy balance, suggesting therapeutic potential for obesity and metabolic diseases.
