REV-ERB in GABAergic neurons controls diurnal hepatic insulin sensitivity

Authors: DING, GUOLIAN - Baylor College Of Medicine; LI, XIN - Baylor College Of Medicine; HOU, XINGUO - Shandong University; ZHOU, WENJUN - Baylor College Of Medicine; GONG, YINGYUN - Baylor College Of Medicine; LIU, FUQIANG - Shandong University; HE, YANLIN - Pennington Biomedical Research Center; SONG, JIA - Shandong University; WANG, JING - Shandong University; BASIL, PAUL - Baylor College Of Medicine; LI, WENBO - Baylor College Of Medicine; QIAN, SICHONG - Baylor College Of Medicine; SAHA, PRADIP - Baylor College Of Medicine; WANG, JINBANG - Shandong University; CUI, CHEN - Shandong University; YANG, TINGTING - Baylor College Of Medicine; ZOU, KEXIN - Fudan University; HAN, YOUNGHUN - Baylor College Of Medicine; AMOS, CHRISTOPHER - Baylor College Of Medicine; XU, YONG - Children'S Nutrition Research Center (CNRC); CHEN, LI - Shandong University; SUN, ZHENG - Baylor College Of Medicine

Submitted to: Nature
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/12/2021
Publication Date: 3/24/2021
Citation: Ding, G., Li, X., Hou, X., Zhou, W., Gong, Y., Liu, F., He, Y., Song, J., Wang, J., Basil, P., Li, W., Qian, S., Saha, P., Wang, J., Cui, C., Yang, T., Zou, K., Han, Y., Amos, C., Xu, Y., Chen, L., Sun, Z. 2021. REV-ERB in GABAergic neurons controls diurnal hepatic insulin sensitivity. Nature. 592:763-767. https://doi.org/10.1038/s41586-021-03358-w.
DOI: https://doi.org/10.1038/s41586-021-03358-w

Interpretive Summary: Some individuals with diabetes experience the extended dawn phenomenon, an increased level of blood glucose after waking. Here, scientist work to understand this phenomenon by studying the nuclear receptors REV-ERB-alpha and REV-ERB-beta. In mice, these receptors control the timing of insulin-mediated suppression of glucose production in the liver. We found a neural pathway, mediated by REV-ERB, which underlies the daily timing of insulin sensitivity in mice. These findings may help future studies to understand the extended dawn phenomenon in individuals with type 2 diabetes.

Technical Abstract: Systemic insulin sensitivity shows a diurnal rhythm with a peak upon waking. The molecular mechanism that underlies this temporal pattern is unclear. Here we show that the nuclear receptors REV-ERB-alpha and REV-ERB-beta (referred to here as 'REV-ERB') in the GABAergic (y-aminobutyric acid-producing) neurons in the suprachiasmatic nucleus (SCN) (SCN^GABA neurons) control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice, without affecting diurnal eating or locomotor behaviours during regular light–dark cycles. REV-ERB regulates the rhythmic expression of genes that are involved in neurotransmission in the SCN, and modulates the oscillatory firing activity of SCN^GABA neurons. Chemogenetic stimulation of SCN^GABA neurons at waking leads to glucose intolerance, whereas restoration of the temporal pattern of either SCN^GABA neuron firing or REV-ERB expression rescues the time-dependent glucose metabolic phenotype caused by REV-ERB depletion. In individuals with diabetes, an increased level of blood glucose after waking is a defining feature of the 'extended dawn phenomenon'. Patients with type 2 diabetes with the extended dawn phenomenon exhibit a differential temporal pattern of expression of REV-ERB genes compared to patients with type 2 diabetes who do not have the extended dawn phenomenon. These findings provide mechanistic insights into how the central circadian clock regulates the diurnal rhythm of hepatic insulin sensitivity, with implications for our understanding of the extended dawn phenomenon in type 2 diabetes.