title: Blunted refeeding response and increased locomotor activity in mice lacking FoxO1 in synapsin-Cre-expressing neurons.
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.
authors.affiliation: Berrie Diabetes Center, New York, New York.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Ren
authors.forename: Leona
authors.initials: L
authors.lastname: Plum-Morschel
authors.forename: Roger
authors.initials: R
authors.lastname: Gutierrez-Juarez
authors.forename: Taylor Y
authors.initials: TY
authors.lastname: Lu
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Kim-Muller
authors.forename: Garrett
authors.initials: G
authors.lastname: Heinrich
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Wardlaw
authors.forename: Rae
authors.initials: R
authors.lastname: Silver
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D015195:Drug Design; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins