Leptin receptor neurons in the dorsomedial hypothalamus regulate diurnal patterns of feeding, locomotion, and metabolism.

Chelsea L Faber,Zaman Mirzadeh,Tammy P Doan,Bao Anh Phan,Kayoko Ogimoto,Michael W Schwartz,Jennifer D Deem,Gregory J Morton

doi:10.7554/elife.63671

Chelsea L Faber, Zaman Mirzadeh + Show 6 more

Open Access

https://doi.org/10.7554/elife.63671

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Abstract

The brain plays an essential role in driving daily rhythms of behavior and metabolism in harmony with environmental light-dark cycles. Within the brain, the dorsomedial hypothalamic nucleus (DMH) has been implicated in the integrative circadian control of feeding and energy homeostasis, but the underlying cell types are unknown. Here, we identify a role for DMH leptin receptor-expressing (DMHLepR) neurons in this integrative control. Using a viral approach, we show that silencing neurotransmission in DMHLepR neurons in adult mice not only increases body weight and adiposity but also phase-advances diurnal rhythms of feeding and metabolism into the light cycle and abolishes the normal increase in dark-cycle locomotor activity characteristic of nocturnal rodents. Finally, DMHLepR-silenced mice fail to entrain to a restrictive change in food availability. Together, these findings identify DMHLepR neurons as critical determinants of the daily time of feeding and associated metabolic rhythms.

Highlights

Synchrony between behavior and environmental rhythms enables animals to predict food availability and optimize metabolism in anticipation of daily periods of fasting and feeding (Saper et al, 2005)
Silencing DMH leptin receptor-expressing (DMHLepR) neurons elicits transient hyperphagia and increased adiposity To determine the role of DMHLepR neurons in feeding and metabolism, we used a viral loss-of-function approach (Figure 1A)
Synaptic neurotransmission by DMHLepR neurons was permanently blocked by bilateral microinjection into the dorsomedial hypothalamic nucleus (DMH) of an adeno-associated virus (AAV) encoding Cre-dependent tetanus toxin light chain fused with a GFP reporter (AAV1-CBA-DIO-GFP: TeTx; Kim et al, 2009; Han et al, 2015; Campos et al, 2017)

Summary

Introduction

Synchrony between behavior and environmental rhythms enables animals to predict food availability and optimize metabolism in anticipation of daily periods of fasting and feeding (Saper et al, 2005). While the hypothalamic suprachiasmatic nucleus (SCN) is well known to entrain circadian rhythmicity in accordance with light–dark cycles, food availability can entrain metabolic rhythms independently from the SCN (Greco and Sassone-Corsi, 2019). Illustrating this point, rodents with SCN lesions exhibit profound disruptions in circadian rhythms, they retain the ability to retrain metabolic and behavioral rhythms in accordance with a scheduled meal (Stephan et al, 1979). Based on recent evidence that DMH neurons expressing leptin receptor (DMHLepR) are both sensitive to food availability and make inhibitory synaptic connections with agouti-related protein (AgRP) neurons to modulate feeding (Garfield et al, 2016), we identified DMHLepR neurons as a candidate population for circadian control of food intake and associated metabolic rhythms

Results and discussion

Conclusion

Materials and methods

Funding Funder National Institutes of Health