Paraventricular hypothalamus mediates diurnal rhythm of metabolism
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 30, 2020
- Source ID
- 10.1038/s41467-020-17578-7
Entities
People
- Aleix Ribas-latre
- Benjamin R Arenkiel
- De-Pei Li
- Eun Ran Kim
- Jinbin Tian
- Kristin Eckel-Mahan
- Mingshan Xue
- Qingchun Tong
- Rachel Van Drunen
- Ryan M. Cassidy
- Yong Xu
- Yongjie Yang
- Yuanzhong Xu
- Yungang Lu
- Zhao-Lin Cai
Organizations
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Neurological Disorders and Stroke
- United States Department of Defense
- United States Department of Health and Human Services