TrkB-expressing neurons in the dorsomedial hypothalamus are necessary and sufficient to suppress homeostatic feeding
Edited by Richard D. Palmiter, University of Washington, Seattle, WA, and approved January 3, 2019 (received for review September 11, 2018)
Significance
The dorsomedial hypothalamus (DMH) is well known for its role in the regulation of energy expenditure; however, its role in the control of appetite is less defined. Our study identifies TrkB-expressing DMH neurons that potently suppress appetite and efficiently maintain physiological satiety when they are activated. Furthermore, because ablating the TrkB receptor in these neurons increased appetite and reduced energy expenditure, our study indicates that BDNF could act in part on the DMH to control body weight. These results suggest that activation of DMH TrkB neurons could be a powerful way to treat obesity because it will not only greatly reduce appetite but also overcome a potent counterregulatory mechanism by which food restriction-induced weight loss disproportionately reduces energy expenditure.
Abstract
Genetic evidence indicates that brain-derived neurotrophic factor (BDNF) signaling through the TrkB receptor plays a critical role in the control of energy balance. Mutations in the BDNF or the TrkB-encoding NTRK2 gene have been found to cause severe obesity in humans and mice. However, it remains unknown which brain neurons express TrkB to control body weight. Here, we report that TrkB-expressing neurons in the dorsomedial hypothalamus (DMH) regulate food intake. We found that the DMH contains both glutamatergic and GABAergic TrkB-expressing neurons, some of which also express the leptin receptor (LepR). As revealed by Fos immunohistochemistry, a significant number of TrkB-expressing DMH (DMHTrkB) neurons were activated upon either overnight fasting or after refeeding. Chemogenetic activation of DMHTrkB neurons strongly suppressed feeding in the dark cycle when mice are physiologically hungry, whereas chemogenetic inhibition of DMHTrkB neurons greatly promoted feeding in the light cycle when mice are physiologically satiated, without affecting feeding in the dark cycle. Neuronal tracing revealed that DMHTrkB neurons do not innervate neurons expressing agouti-related protein in the arcuate nucleus, indicating that DMHTrkB neurons are distinct from previously identified LepR-expressing GABAergic DMH neurons that suppress feeding. Furthermore, selective Ntrk2 deletion in the DMH of adult mice led to hyperphagia, reduced energy expenditure, and obesity. Thus, our data show that DMHTrkB neurons are a population of neurons that are necessary and sufficient to suppress appetite and maintain physiological satiation. Pharmacological activation of these neurons could be a therapeutic intervention for the treatment of obesity.
Acknowledgments
We thank Dr. David Ginty for the Ntrk2CreER mouse strain and Jessica Houtz, Shaw-wen Wu, and Xiangyang Xie for critical reading of this manuscript. This work was supported by National Institutes of Health Grants R01 DK105954 and R01 DK103335 (to B.X.).
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© 2019. Published under the PNAS license.
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Published online: February 4, 2019
Published in issue: February 19, 2019
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Acknowledgments
We thank Dr. David Ginty for the Ntrk2CreER mouse strain and Jessica Houtz, Shaw-wen Wu, and Xiangyang Xie for critical reading of this manuscript. This work was supported by National Institutes of Health Grants R01 DK105954 and R01 DK103335 (to B.X.).
Notes
This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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TrkB-expressing neurons in the dorsomedial hypothalamus are necessary and sufficient to suppress homeostatic feeding, Proc. Natl. Acad. Sci. U.S.A.
116 (8) 3256-3261,
https://doi.org/10.1073/pnas.1815744116
(2019).
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