REV-ERB in GABAergic neurons controls diurnal hepatic insulin sensitivity

Ding, Guo‐Lian; Li, Xin; Hou, Xinguo; Zhou, Wolong; Gong, Yingyun; Liu, Fuqiang; He, Yanlin; Song, Jia; Wang, Jing; Basil, Paul; Li, Wenbo; Qian, Sichong; Saha, Pradip Kumar; Wang, Jinbang; Cui, Chen; Yang, Tingting; Zou, Kexin; Han, Younghun; Amos, Christopher I.; Xu, Yong; Chen, Li; Sun, Zheng

doi:10.1038/s41586-021-03358-w

Cited by 47 publications

(38 citation statements)

References 54 publications

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“…3F). This finding—that the central clock suffices for glucose homeostasis—complements recent work showing that it is necessary for glucose homeostasis ( 28 ). Together, these results underscore the importance of central processes in regulating glucose homeostasis and expands on the knowledge linking shift work to diabetes ( 29 ).…”

Section: Mainsupporting

confidence: 81%

The central clock suffices to drive the majority of circulatory metabolic rhythms

Petrus

Smith

Koronowski

et al. 2022

Preprint

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Life on Earth anticipates recurring 24-h environmental cycles via genetically-encoded molecular clocks active in all mammalian organs. Communication between these clocks is believed to control circadian homeostasis. Metabolism can be considered a form of inter-tissue communication language that results in temporal coordination of systemic metabolism between tissues. Here we characterize the extent to which clocks in different organs employ this means of communication, an area which remains largely unexplored. For this, we analysed the metabolome of serum from mice with tissue-specific expression of the clock gene Bmal1. Notably, having functional hepatic and muscle clocks can only drive a minority (13%) of the oscillating metabolites in circulation. Conversely, limiting Bmal1 expression to Syt10-expressing neurons (which are enriched in the suprachiasmatic nucleus [SCN], the master pacemaker that regulates circadian rhythms) restores rhythms to 57% of circulatory metabolites and 28% of liver transcripts, and rescues glucose intolerance. Importantly, these parameters were also restored in clock-less mice upon rhythmic feeding, indicating that the central clock mainly regulates metabolic rhythms via behavior. These findings explicate the circadian communication between tissues and highlight the importance of the central clock in governing those signals.

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Section: Mainsupporting

confidence: 81%

The central clock suffices to drive the majority of circulatory metabolic rhythms

Petrus

Smith

Koronowski

et al. 2022

Preprint

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“…However, altered expression of these clock genes has been shown to induce changes in the glycometabolic profile. 17,19 We believe that growth hormone deficiency and the lack of nocturnal growth hormone surges alone are insufficient to explain insulin sensitivity in our case.…”

Section: Discussionmentioning

confidence: 69%

“…Ding et al have demonstrated differential expression of nuclear receptors in the suprachiasmatic nucleus which controls the diurnal rhythm of insulin sensitivity. 17 Similarly, the diurnal variation in free fatty acid availability governed by previous meals and diurnal expression of the PDK4 gene responsible for the availability of free fatty acids govern insulin sensitivity. 18 It is not known if cytotoxic chemotherapy and radiotherapy, which work by inducing DNA, can disrupt the intrinsic circadian rhythm leading to insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

Severe insulin resistance in long-term acute leukaemia survivors: lesson learned from a clinical case and review of the literature

Bashir

Banerjee

2021

Br J Diabetes

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With the improvement of haematopoietic stem cell transplantation (HSCT) and radiotherapy, the population of cancer survivors is increasing and therefore increasing the number of patients living with late metabolic complications. We describe a case of a childhood acute lymphoblastic leukaemia survivor who developed insulin resistance 10 years after HSCT and total body radiation requiring a high dose of insulin (>1,500 IU). Using insulin-sensitising agents metformin and thiazolidinediones improved the control and reduced the insulin requirement – eventually stopping insulin. We describe for the first time the phenomenon of reverse diurnal variation in insulin sensitivity based on the clinical picture alone, which has not previously been described in the literature. We have reviewed the plausible mechanisms of developing insulin resistance, reverse diurnal variation and the role of thiazolidinediones in reducing lipotoxicity and adipocyte differentiation resulting in improved insulin sensitivity in such cases.

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“…Moreover, targeted deletion of Bmal1 in neurons and glia was found to exacerbate neurodegenerative pathologies and behaviors, despite the retention of intact circadian behavioral and sleep–wake rhythms under LD conditions [ 101 ]. In line with these findings, a recent study showed that the nuclear receptors Rev-erbα/β in the GABAergic (γ-aminobutyric acid-producing) in neurons of the SCN (SCN GABA neurons) control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice, without affecting diurnal eating or locomotor behaviors during regular light–dark cycles [ 113 ]. These results suggest that the SCN central clock plays an important role in maintaining the internal synchrony of robust circadian programs in some peripheral clocks, while other peripheral clocks can be differentially modulated by light and feeding, regardless of the presence of a functional SCN central oscillator in the brain.…”

Section: The Role Of Brain Clocks In Circadian Rhythms and Disordersmentioning

confidence: 85%

Multi-Modal Regulation of Circadian Physiology by Interactive Features of Biological Clocks

Lee

Wisor

2021

Biology

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The circadian clock is a fundamental biological timing mechanism that generates nearly 24 h rhythms of physiology and behaviors, including sleep/wake cycles, hormone secretion, and metabolism. Evolutionarily, the endogenous clock is thought to confer living organisms, including humans, with survival benefits by adapting internal rhythms to the day and night cycles of the local environment. Mirroring the evolutionary fitness bestowed by the circadian clock, daily mismatches between the internal body clock and environmental cycles, such as irregular work (e.g., night shift work) and life schedules (e.g., jet lag, mistimed eating), have been recognized to increase the risk of cardiac, metabolic, and neurological diseases. Moreover, increasing numbers of studies with cellular and animal models have detected the presence of functional circadian oscillators at multiple levels, ranging from individual neurons and fibroblasts to brain and peripheral organs. These oscillators are tightly coupled to timely modulate cellular and bodily responses to physiological and metabolic cues. In this review, we will discuss the roles of central and peripheral clocks in physiology and diseases, highlighting the dynamic regulatory interactions between circadian timing systems and multiple metabolic factors.

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REV-ERB in GABAergic neurons controls diurnal hepatic insulin sensitivity

Cited by 47 publications

References 54 publications

The central clock suffices to drive the majority of circulatory metabolic rhythms

The central clock suffices to drive the majority of circulatory metabolic rhythms

Severe insulin resistance in long-term acute leukaemia survivors: lesson learned from a clinical case and review of the literature

Multi-Modal Regulation of Circadian Physiology by Interactive Features of Biological Clocks

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