Paraventricular hypothalamus mediates diurnal rhythm of metabolism

Eun Ran Kim, Yuanzhong Xu, Ryan M. Cassidy, Yungang Lu, Yongjie Yang, Jinbin Tian, Li De-Pei, Rachel Van Drunen, Aleix Ribas-Latre, Zhao-Lin Cai, Mingshan Xue, Benjamin R. Arenkiel, Kristin Eckel-Mahan, Yong Xu and Qingchun Tong ()
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Eun Ran Kim: University of Texas McGovern Medical School
Yuanzhong Xu: University of Texas McGovern Medical School
Ryan M. Cassidy: University of Texas McGovern Medical School
Yungang Lu: University of Texas McGovern Medical School
Yongjie Yang: Baylor College of Medicine
Jinbin Tian: University of Texas McGovern Medical School
Li De-Pei: University of Texas MD Anderson Cancer Center
Rachel Van Drunen: University of Texas McGovern Medical School
Aleix Ribas-Latre: University of Texas McGovern Medical School
Zhao-Lin Cai: Baylor College of Medicine
Mingshan Xue: Baylor College of Medicine
Benjamin R. Arenkiel: Baylor College of Medicine
Kristin Eckel-Mahan: University of Texas McGovern Medical School
Yong Xu: Baylor College of Medicine
Qingchun Tong: University of Texas McGovern Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17578-7

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