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. 2012;7(2):e31487.
doi: 10.1371/journal.pone.0031487. Epub 2012 Feb 2.

InsR/FoxO1 Signaling Curtails Hypothalamic POMC Neuron Number

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Free PMC article

InsR/FoxO1 Signaling Curtails Hypothalamic POMC Neuron Number

Leona Plum et al. PLoS One. .
Free PMC article

Abstract

Insulin receptor (InsR) signaling through transcription factor FoxO1 is important in the development of hypothalamic neuron feeding circuits, but knowledge about underlying mechanisms is limited. To investigate the role of InsR/FoxO1 signaling in the development and maintenance of these circuits, we surveyed the pool of hypothalamic neurons expressing Pomc mRNA in different mouse models of impaired hypothalamic InsR signaling. InsR ablation in the entire hypothalamus did not affect Pomc-neuron number at birth, but resulted in a 25% increase, most notably in the middle arcuate nucleus region, in young adults. Selective restoration of InsR expression in POMC neurons in these mice partly reversed the abnormality, resulting in a 10% decrease compared to age-matched controls. To establish whether FoxO1 signaling plays a role in this process, we examined POMC neuron number in mice with POMC-specific deletion of FoxO1, and detected a 23% decrease in age-matched animals, consistent with a cell-autonomous role of InsR/FoxO1 signaling in regulating POMC neuron number, distinct from its established role to activate Pomc transcription. These changes in Pomc cells occurred in the absence of marked changes in humoral factors or hypothalamic NPY neurons.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Schematic diagrams of the hypothalamus of mouse models used in this study.
3V, third ventricle; ARC, arcuate nucleus of the hypothalamus. Recombination in POMC neurons of L1-Pomc+InsR and Pomc–Foxo1 mice is induced by a Pomc-Cre transgene.
Figure 2
Figure 2. InsR affects Pomc but not Npy neuron numbers in adult L1 mice.
Number of Pomc-expressing (A) and Npy-expressing (B) cells per ARC hemisection in L1 mice (grey bars, n = 5) and WT controls (white bars, n = 5) at the age of 15 weeks. Number of Pomc-expressing cells per ARC hemisection in the same mice as in A compared to L1-Pomc+InsR (yellow bars, n = 6) at the age of 15 weeks (C). Exemplary Pomc FISH pictures of WT, L1, and L1-Pomc+InsR mice (D). Scale bar is 100 µm. All data are means ± S.E.M.. *P<0.05 L1 vs. WT control. #P<0.05 L1 vs. L1-Pomc+InsR.
Figure 3
Figure 3. Reduced Pomc and unaltered Npy neuron number in adult Pomc–Foxo1 mice.
Number of Pomc-expressing (A) and Npy-expressing (B) cells per ARC hemisection in Pomc–Foxo1 mice (black bars, n = 7–9) and WT controls (white bars, n = 7–9) at the age of 15 weeks. Exemplary Pomc FISH pictures of two WT and Pomc–Foxo1 mice (C). Scale bar is 100 µm. All data are means ± S.E.M. *P<0.05 vs. WT control.

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