FOXO1 in the ventromedial hypothalamus regulates energy balance
Ki Woo Kim, Jose Donato Jr., Eric D. Berglund, Yun-Hee Choi, Daisuke Kohno, Carol F. Elias, Ronald A. DePinho, Joel K. Elmquist
Ki Woo Kim, Jose Donato Jr., Eric D. Berglund, Yun-Hee Choi, Daisuke Kohno, Carol F. Elias, Ronald A. DePinho, Joel K. Elmquist
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Research Article Metabolism

FOXO1 in the ventromedial hypothalamus regulates energy balance

Abstract

The transcription factor FOXO1 plays a central role in metabolic homeostasis by regulating leptin and insulin activity in many cell types, including neurons. However, the neurons mediating these effects and the identity of the molecular targets through which FOXO1 regulates metabolism remain to be defined. Here, we show that the ventral medial nucleus of the hypothalamus (VMH) is a key site of FOXO1 action. We found that mice lacking FOXO1 in steroidogenic factor 1 (SF-1) neurons of the VMH are lean due to increased energy expenditure. The mice also failed to appropriately suppress energy expenditure in response to fasting. Furthermore, these mice displayed improved glucose tolerance due to increased insulin sensitivity in skeletal muscle and heart. Gene expression profiling and sequence analysis revealed several pathways regulated by FOXO1. In addition, we identified the nuclear receptor SF-1 as a direct FOXO1 transcriptional target in the VMH. Collectively, our data suggest that the transcriptional networks modulated by FOXO1 in VMH neurons are key components in the regulation of energy balance and glucose homeostasis.

Authors

Ki Woo Kim, Jose Donato Jr., Eric D. Berglund, Yun-Hee Choi, Daisuke Kohno, Carol F. Elias, Ronald A. DePinho, Joel K. Elmquist

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Figure 3

Effect of VMH-specific FOXO1 KO in body weight, UCP1 levels, and plasma catecholamines.

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Effect of VMH-specific FOXO1 KO in body weight, UCP1 levels, and plasma ...
(A) Body weight of male mice fed with HFD from 5 weeks. (B) Body composition (11–12 weeks old) of male mice fed HFD. (C) Temporal changes of O2 consumption before and after the acute HFD challenge. (D) Changes in O2 consumption before and after HFD. (E) Ucp1 mRNA levels in iBAT from male mice fed NC (6–7 weeks old). (F) Individual UCP1 protein levels in iBAT of WT and Foxo1 KOSf1 littermates (6–7 weeks old). (G) Average UCP1 protein levels in iBAT of WT and Foxo1 KOSf1 counterparts (6–7 weeks old). (H) Plasma norepinephrine and epinephrine in chow-fed males (7–8 weeks old). Numbers of animals examined were expressed in parentheses in each graph. The data are expressed as either (C) average or mean ± SEM (*P < 0.05, **P < 0.01, Student’s t test). WT, Foxo1F/F; KO, Foxo1 KOSf1; Ucp, uncoupling protein.