Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice
David E.G. McNay, … , Eleftheria Maratos-Flier, Jeffrey S. Flier
David E.G. McNay, … , Eleftheria Maratos-Flier, Jeffrey S. Flier
Published December 27, 2011
Citation Information: J Clin Invest. 2012;122(1):142-152. https://doi.org/10.1172/JCI43134.
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Research Article

Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice

Abstract

In the CNS, the hypothalamic arcuate nucleus (ARN) energy-balance circuit plays a key role in regulating body weight. Recent studies have shown that neurogenesis occurs in the adult hypothalamus, revealing that the ARN energy-balance circuit is more plastic than originally believed. Changes in diet result in altered gene expression and neuronal activity in the ARN, some of which may reflect hypothalamic plasticity. To explore this possibility, we examined the turnover of hypothalamic neurons in mice with obesity secondary to either high-fat diet (HFD) consumption or leptin deficiency. We found substantial turnover of neurons in the ARN that resulted in ongoing cellular remodeling. Feeding mice HFD suppressed neurogenesis, as demonstrated by the observation that these mice both generated fewer new neurons and retained more old neurons. This suppression of neuronal turnover was associated with increased apoptosis of newborn neurons. Leptin-deficient mice also generated fewer new neurons, an observation that was explained in part by a loss of hypothalamic neural stem cells. These data demonstrate that there is substantial postnatal turnover of the arcuate neuronal circuitry in the mouse and reveal the unexpected capacity of diet and leptin deficiency to inhibit this neuronal remodeling. This insight has important implications for our understanding of nutritional regulation of energy balance and brain function.

Authors

David E.G. McNay, Nadege Briançon, Maia V. Kokoeva, Eleftheria Maratos-Flier, Jeffrey S. Flier

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Figure 2

ARN energy-balance neurons are turned over by ongoing neurogenesis.

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ARN energy-balance neurons are turned over by ongoing neurogenesis. (A–C...
(A–C) Nuclei labeled with BrdU (red) at E10.5 remaining in the ARN at 4, 12, and 26 weeks, counterstained with DAPI (blue). (D) Quantification of ARN neuron survival, showing that labeled ARN neurons were lost between 4 and 12 weeks of age but not between 12 and 26 weeks of age. (E–G) POMC neurons (green) labeled with BrdU (red) at E10.5 remaining in the ARN at 4, 12, and 26 weeks. (H) Quantification of POMC neuron survival, showing that labeled POMC neurons were lost between 4 and 12 weeks of age but not between 12 and 26 weeks of age. (I–K) NPY neurons (green) labeled with BrdU (red) at E10.5 remaining in the ARN at 4, 12, and 26 weeks. We made use of NPY-hrGFP mice to reveal NPY neurons. (L) Quantification of NPY neuron survival, showing that labeled NPY neurons were lost between 4 and 12 weeks of age but not between 12 and 26 weeks of age. (M–O) Nuclei labeled with BrdU (red) at E10.5 remaining in the amygdala at 4, 12, and 26 weeks, counterstained with DAPI (blue). (P) Quantification of amygdala neuron survival, showing that labeled amygdala neurons were not lost between 4 and 12 weeks of age or between 12 and 26 weeks of age. (Columns indicate total cell counts as a percentage of cell count at 4 weeks.) *P < 0.05 compared with 4 weeks; #P < 0.05 compared with 12 weeks. (Q) Schematic of analysis. Mean ± SEM; n = 10–19 at 4 weeks, 7–11 at 12 weeks, 4–9 at 26 weeks. Scale bar: 100 μm.