Paraventricular Hypothalamus Mediates Diurnal Rhythm of Metabolism

Authors

Eun Ran Kim
Yuanzhong Xu
Ryan M Cassidy
Yungang Lu
Yongjie Yang
Jinbin Tian
De-Pei Li
Rachel Van Drunen
Aleix Ribas-Latre
Zhao-Lin Cai
Mingshan Xue
Benjamin R Arenkiel
Kristin Eckel-Mahan
Yong Xu
Qingchun Tong

Publication Date

7-30-2020

Journal

Nature Communications

DOI

10.1038/s41467-020-17578-7

PMID

32732906

PMCID

PMC7393104

PubMedCentral® Posted Date

7-30-2020

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

ARNTL Transcription Factors, Animals, Circadian Rhythm, Diet, High-Fat, Energy Metabolism, Feeding Behavior, Mice, Mice, Knockout, Neurons, Obesity, Paraventricular Hypothalamic Nucleus, Receptors, GABA-A, Obesity, Metabolic disorders, Endocrinology

Abstract

Defective rhythmic metabolism is associated with high-fat high-caloric diet (HFD) feeding, ageing and obesity; however, the neural basis underlying HFD effects on diurnal metabolism remains elusive. Here we show that deletion of BMAL1, a core clock gene, in paraventricular hypothalamic (PVH) neurons reduces diurnal rhythmicity in metabolism, causes obesity and diminishes PVH neuron activation in response to fast-refeeding. Animal models mimicking deficiency in PVH neuron responsiveness, achieved through clamping PVH neuron activity at high or low levels, both show obesity and reduced diurnal rhythmicity in metabolism. Interestingly, the PVH exhibits BMAL1-controlled rhythmic expression of GABA-A receptor γ2 subunit, and dampening rhythmicity of GABAergic input to the PVH reduces diurnal rhythmicity in metabolism and causes obesity. Finally, BMAL1 deletion blunts PVH neuron responses to external stressors, an effect mimicked by HFD feeding. Thus, BMAL1-driven PVH neuron responsiveness in dynamic activity changes involving rhythmic GABAergic neurotransmission mediates diurnal rhythmicity in metabolism and is implicated in diet-induced obesity.