A salt-induced kinase (SIK) is required for the metabolic regulation of sleep

Mapping Intimacies ◽

10.1101/586701 ◽

2019 ◽

Cited By ~ 4

Author(s):

Jeremy J. Grubbs ◽

Lindsey E. Lopes ◽

Alexander M. van der Linden ◽

David M. Raizen

Keyword(s):

Histone Deacetylase ◽

Sensory Neurons ◽

Metabolic Regulation ◽

Energy Homeostasis ◽

Energy Charge ◽

Cellular Energy ◽

C Elegans ◽

Atp Levels ◽

Energy Stores ◽

Fat Stores

ABSTRACTMany lines of evidence point to links between sleep regulation and energy homeostasis, but mechanisms underlying these connections are unknown. During C. elegans sleep, energetic stores are allocated to non-neural tasks with a resultant drop in the overall fat stores and energy charge. Mutants lacking KIN-29, the C. elegans homolog of a mammalian Salt-Inducible Kinase (SIK) that signals sleep pressure, have low ATP levels despite high fat stores, indicating a defective response to cellular energy deficits. Liberating energy stores corrects adiposity and sleep defects of kin-29 mutants. kin-29 sleep and energy homeostasis roles map to a small number of sensory neurons that act upstream of fat regulation as well as of central sleep-controlling neurons, suggesting hierarchical somatic/neural interactions regulating sleep and energy homeostasis. Genetic interaction between kin-29 and the histone deacetylase hda-4 coupled with subcellular localization studies indicate that KIN-29 acts in the nucleus to regulate sleep. We propose that KIN-29/SIK acts in nuclei of sensory neuroendocrine cells to transduce low cellular energy charge into the mobilization of energy stores, which in turn promotes sleep.HighlightsSleep is associated with fat mobilization and low ATP levelsMetabolic regulation of sleep requires the salt-induced kinase (SIK) homolog KIN-29KIN-29 acts in sensory neurons upstream of sleep-promoting neuronsNuclear localization of KIN-29 is required for the metabolic regulation of sleepA type 2 histone deacetylase acts down stream of KIN-29 in the regulation of sleep.Liberation of energy from fat-storage cells promotes sleep.Beta-oxidation promotes sleep.

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Regulation of axonal morphogenesis by the mitochondrial protein Efhd1

Life Science Alliance ◽

10.26508/lsa.202000753 ◽

2020 ◽

Vol 3 (7) ◽

pp. e202000753 ◽

Cited By ~ 1

Author(s):

Valeria Ulisse ◽

Swagata Dey ◽

Deborah E Rothbard ◽

Einav Zeevi ◽

Irena Gokhman ◽

...

Keyword(s):

Sensory Neurons ◽

Energy Homeostasis ◽

Mitochondrial Protein ◽

Axonal Growth ◽

Autophagic Flux ◽

Genetic Ablation ◽

Atp Levels ◽

Ef Hand ◽

Liver Kinase B1 ◽

Amp Activated Protein Kinase

During development, neurons adjust their energy balance to meet the high demands of robust axonal growth and branching. The mechanisms that regulate this tuning are largely unknown. Here, we show that sensory neurons lacking liver kinase B1 (Lkb1), a master regulator of energy homeostasis, exhibit impaired axonal growth and branching. Biochemical analysis of these neurons revealed reduction in axonal ATP levels, whereas transcriptome analysis uncovered down-regulation of Efhd1 (EF-hand domain family member D1), a mitochondrial Ca2+-binding protein. Genetic ablation of Efhd1 in mice resulted in reduced axonal morphogenesis as well as enhanced neuronal death. Strikingly, this ablation causes mitochondrial dysfunction and a decrease in axonal ATP levels. Moreover, Efhd1 KO sensory neurons display shortened mitochondria at the axonal growth cones, activation of the AMP-activated protein kinase (AMPK)–Ulk (Unc-51–like autophagy-activating kinase 1) pathway and an increase in autophagic flux. Overall, this work uncovers a new mitochondrial regulator that is required for axonal morphogenesis.

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Sirtuin 1 and Sirtuin 3: Physiological Modulators of Metabolism

Physiological Reviews ◽

10.1152/physrev.00022.2011 ◽

2012 ◽

Vol 92 (3) ◽

pp. 1479-1514 ◽

Cited By ~ 309

Author(s):

Ruben Nogueiras ◽

Kirk M. Habegger ◽

Nilika Chaudhary ◽

Brian Finan ◽

Alexander S. Banks ◽

...

Keyword(s):

Energy Homeostasis ◽

Sirtuin 1 ◽

Energy Status ◽

Metabolic Processes ◽

Sirtuin 3 ◽

Nonalcoholic Fatty Liver ◽

Cellular Energy ◽

Diet Induced Obesity ◽

Energy Stores

The sirtuins are a family of highly conserved NAD+-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD+ levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.

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The ETS-5 transcription factor regulates activity states in Caenorhabditis elegans by controlling satiety

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1610673114 ◽

2017 ◽

Vol 114 (9) ◽

pp. E1651-E1658 ◽

Cited By ~ 19

Author(s):

Vaida Juozaityte ◽

David Pladevall-Morera ◽

Agnieszka Podolska ◽

Steffen Nørgaard ◽

Brent Neumann ◽

...

Keyword(s):

Transcription Factor ◽

Caenorhabditis Elegans ◽

Sensory Neurons ◽

Animal Behavior ◽

Major Influence ◽

Behavioral State ◽

C Elegans ◽

State Switching ◽

Control Food ◽

Fat Stores

Animal behavior is shaped through interplay among genes, the environment, and previous experience. As in mammals, satiety signals induce quiescence in Caenorhabditis elegans. Here we report that the C. elegans transcription factor ETS-5, an ortholog of mammalian FEV/Pet1, controls satiety-induced quiescence. Nutritional status has a major influence on C. elegans behavior. When foraging, food availability controls behavioral state switching between active (roaming) and sedentary (dwelling) states; however, when provided with high-quality food, C. elegans become sated and enter quiescence. We show that ETS-5 acts to promote roaming and inhibit quiescence by setting the internal “satiety quotient” through fat regulation. Acting from the ASG and BAG sensory neurons, we show that ETS-5 functions in a complex network with serotonergic and neuropeptide signaling pathways to control food-regulated behavioral state switching. Taken together, our results identify a neuronal mechanism for controlling intestinal fat stores and organismal behavioral states in C. elegans, and establish a paradigm for the elucidation of obesity-relevant mechanisms.

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The G Protein regulators EGL-10 and EAT-16, the Giα GOA-1 and the Gqα EGL-30 modulate the response of the C. elegans ASH polymodal nociceptive sensory neurons to repellents

BMC Biology ◽

10.1186/1741-7007-8-138 ◽

2010 ◽

Vol 8 (1) ◽

pp. 138 ◽

Cited By ~ 18

Author(s):

Giovanni Esposito ◽

Maria R Amoroso ◽

Carmela Bergamasco ◽

Elia Di Schiavi ◽

Paolo Bazzicalupo

Keyword(s):

G Protein ◽

Sensory Neurons ◽

C Elegans

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Metabolic Regulation of Hippocampal Neuronal Development and Its Inhibition After Irradiation

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab014 ◽

2021 ◽

Vol 80 (5) ◽

pp. 467-475

Author(s):

Yu-Qing Li ◽

C Shun Wong

Keyword(s):

Cell Fate ◽

Metabolic Regulation ◽

Energy Homeostasis ◽

Neuronal Development ◽

Adenosine Monophosphate ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Wild Type ◽

Newborn Neuron ◽

Negative Effect

Abstract 5′-Adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, plays a role in cell fate determination. Whether AMPK regulates hippocampal neuronal development remains unclear. Hippocampal neurogenesis is abrogated after DNA damage. Here, we asked whether AMPK regulates adult hippocampal neurogenesis and its inhibition following irradiation. Adult Cre-lox mice deficient in AMPK in brain, and wild-type mice were used in a birth-dating study using bromodeoxyuridine to evaluate hippocampal neurogenesis. There was no evidence of AMPK or phospho-AMPK immunoreactivity in hippocampus. Increase in p-AMPK but not AMPK expression was observed in granule neurons and subgranular neuroprogenitor cells (NPCs) in the dentate gyrus within 24 hours and persisted up to 9 weeks after irradiation. AMPK deficiency in Cre-lox mice did not alter neuroblast and newborn neuron numbers but resulted in decreased newborn and proliferating NPCs. Inhibition of neurogenesis was observed after irradiation regardless of genotypes. In Cre-lox mice, there was further loss of newborn early NPCs and neuroblasts but not newborn neurons after irradiation compared with wild-type mice. These results are consistent with differential negative effect of AMPK on hippocampal neuronal development and its inhibition after irradiation.

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AMP-activated protein kinase - the key sensor of cellular energy charge

Journal of Molecular and Cellular Cardiology ◽

10.1016/s0022-2828(01)90559-0 ◽

2001 ◽

Vol 33 (6) ◽

pp. A146 ◽

Cited By ~ 1

Author(s):

D.Grahame Hardie

Keyword(s):

Protein Kinase ◽

Energy Charge ◽

Cellular Energy ◽

Amp Activated Protein Kinase

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Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases

Nature Communications ◽

10.1038/s41467-020-20269-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Mercedes M. Pérez-Jiménez ◽

José M. Monje-Moreno ◽

Ana María Brokate-Llanos ◽

Mónica Venegas-Calerón ◽

Alicia Sánchez-García ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Caenorhabditis Elegans ◽

Protein Aggregation ◽

Steroid Hormones ◽

Sensory Neurons ◽

Environmental Cues ◽

Steroid Sulfatase ◽

Loss Of Function ◽

C Elegans ◽

Age Related

AbstractAging and fertility are two interconnected processes. From invertebrates to mammals, absence of the germline increases longevity. Here we show that loss of function of sul-2, the Caenorhabditis elegans steroid sulfatase (STS), raises the pool of sulfated steroid hormones, increases longevity and ameliorates protein aggregation diseases. This increased longevity requires factors involved in germline-mediated longevity (daf-16, daf-12, kri-1, tcer-1 and daf-36 genes) although sul-2 mutations do not affect fertility. Interestingly, sul-2 is only expressed in sensory neurons, suggesting a regulation of sulfated hormones state by environmental cues. Treatment with the specific STS inhibitor STX64, as well as with testosterone-derived sulfated hormones reproduces the longevity phenotype of sul-2 mutants. Remarkably, those treatments ameliorate protein aggregation diseases in C. elegans, and STX64 also Alzheimer’s disease in a mammalian model. These results open the possibility of reallocating steroid sulfatase inhibitors or derivates for the treatment of aging and aging related diseases.

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Polymodal Functionality of C. elegans OLL Neurons in Mechanosensation and Thermosensation

Neuroscience Bulletin ◽

10.1007/s12264-021-00629-4 ◽

2021 ◽

Author(s):

Yuedan Fan ◽

Wenjuan Zou ◽

Jia Liu ◽

Umar Al-Sheikh ◽

Hankui Cheng ◽

...

Keyword(s):

Glutamate Receptor ◽

Sensory Neurons ◽

Molecular Mechanisms ◽

Temperature Sensitive ◽

Cold Sensation ◽

Cold Response ◽

C Elegans ◽

Sensory Modalities ◽

A Cell ◽

Bona Fide

AbstractSensory modalities are important for survival but the molecular mechanisms remain challenging due to the polymodal functionality of sensory neurons. Here, we report the C. elegans outer labial lateral (OLL) sensilla sensory neurons respond to touch and cold. Mechanosensation of OLL neurons resulted in cell-autonomous mechanically-evoked Ca2+ transients and rapidly-adapting mechanoreceptor currents with a very short latency. Mechanotransduction of OLL neurons might be carried by a novel Na+ conductance channel, which is insensitive to amiloride. The bona fide mechano-gated Na+-selective degenerin/epithelial Na+ channels, TRP-4, TMC, and Piezo proteins are not involved in this mechanosensation. Interestingly, OLL neurons also mediated cold but not warm responses in a cell-autonomous manner. We further showed that the cold response of OLL neurons is not mediated by the cold receptor TRPA-1 or the temperature-sensitive glutamate receptor GLR-3. Thus, we propose the polymodal functionality of OLL neurons in mechanosensation and cold sensation.

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Discovery of InsP6-kinases as InsP6-dephosphorylating enzymes provides a new mechanism of cytosolic InsP6 degradation driven by the cellular ATP/ADP ratio

Biochemical Journal ◽

10.1042/bj20130992 ◽

2014 ◽

Vol 462 (1) ◽

pp. 173-184 ◽

Cited By ~ 34

Author(s):

Torsten Wundenberg ◽

Nicole Grabinski ◽

Hongying Lin ◽

Georg W. Mayr

Keyword(s):

Energy Charge ◽

Inositol Hexakisphosphate ◽

Cellular Energy

Inositol hexakisphosphate (InsP6) kinases are identified as InsP6 phosphorylating and dephosphorylating enzymes synthesizing either 5PP-InsP5 or Ins(2,3,4,5,6)P5. Their respective activity for InsP6 is dependent on the ATP/ADP ratio, thus acting as a cellular energy charge sensor.

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