AMP-Activated Kinase Links Serotonergic Signaling to Glutamate Release for Regulation of Feeding Behavior in C. elegans

Department of Physiology, University of California, San Francisco, San Francisco, CA 94158-2517, USA.
Cell metabolism (Impact Factor: 17.57). 07/2012; 16(1):113-21. DOI: 10.1016/j.cmet.2012.05.014
Source: PubMed

ABSTRACT Serotonergic regulation of feeding behavior has been studied intensively, both for an understanding of the basic neurocircuitry of energy balance in various organisms and as a therapeutic target for human obesity. However, its underlying molecular mechanisms remain poorly understood. Here, we show that neural serotonin signaling in C. elegans modulates feeding behavior through inhibition of AMP-activated kinase (AMPK) in interneurons expressing the C. elegans counterpart of human SIM1, a transcription factor associated with obesity. In turn, glutamatergic signaling links these interneurons to pharyngeal neurons implicated in feeding behavior. We show that AMPK-mediated regulation of glutamatergic release is conserved in rat hippocampal neurons. These findings reveal cellular and molecular mediators of serotonergic signaling.

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    • "Moreover, the extent of fasting-induced hyperactive feeding was reminiscent of the effects of treatment of wellfed animals with exogenous serotonin or serotonin reuptake inhibitors (Horvitz et al., 1982; Avery and Horvitz, 1990; Srinivasan et al., 2008). Serotonin-induced hyperactive feeding is dependent on the serotonergic GPCR, SER-5, and consequent inactivation of an AMP-activated kinase (AMPK) complex encoded by aak-2 in a pair of interneurons that selectively express the obesity-associated transcription factor, Sim-1/HLH-34 (pathway summarized in Figure S1A) (Cunningham et al., 2012). Loss-offunction mutants of ser-5 and hlh-34 exhibited wild-type pumping rates during the ad-libitum-fed and -fasted states but failed to hyperactivate pumping post-fast (Figure 1B). "
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    ABSTRACT: The kynurenine pathway of tryptophan metabolism is involved in the pathogenesis of several brain diseases, but its physiological functions remain unclear. We report that kynurenic acid, a metabolite in this pathway, functions as a regulator of food-dependent behavioral plasticity in C. elegans. The experience of fasting in C. elegans alters a variety of behaviors, including feeding rate, when food is encountered post-fast. Levels of neurally produced kynurenic acid are depleted by fasting, leading to activation of NMDA-receptor-expressing interneurons and initiation of a neuropeptide-y-like signaling axis that promotes elevated feeding through enhanced serotonin release when animals re-encounter food. Upon refeeding, kynurenic acid levels are eventually replenished, ending the elevated feeding period. Because tryptophan is an essential amino acid, these findings suggest that a physiological role of kynurenic acid is in directly linking metabolism to activity of NMDA and serotonergic circuits, which regulate a broad range of behaviors and physiologies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 01/2015; 160(1-2):119-131. DOI:10.1016/j.cell.2014.12.028 · 32.24 Impact Factor
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    • "However, the specific role of aak-2 in regulation of dauer fat has more recently been called into question as it was shown that aak-2 mutants have reduced fat levels at all stages and that reconstitution of aak-2 in the nervous system only was sufficient to confer normal fat storage to aak-2 mutants (Cunningham et al., 2014). Elevated serotonin signaling leads to inactivation of neural AAK-2 (Cunningham et al., 2012) and promotes a neuroendocrine cascade leading to peripheral fat reduction due to enhanced fat oxidation (Cunningham et al., 2014; Srinivasan et al., 2008). Consistent with this, atgl transcription was shown to be upregulated upon elevation of serotonin (Noble et al., 2013) providing an alternative explanation for the observed regulatory link between AMPK and ATGL. "
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    ABSTRACT: Abstract C. elegans provides a genetically tractable system for deciphering the homeostatic mechanisms that underlie fat regulation in intact organisms. Here, we provide an overview of the recent advances in the C. elegans fat field with particular attention to studies of C. elegans lipid droplets, the complex links between lipases, autophagy, and lifespan, and analyses of key transcriptional regulatory mechanisms that coordinate lipid homeostasis. These studies demonstrate the ancient origins of mammalian and C. elegans fat regulatory pathways and highlight how C. elegans is being used to identify and analyze novel lipid pathways that are then shown to function similarly in mammals. Despite its many advantages, study of fat regulation in C. elegans is currently faced with a number of conceptual and methodological challenges. We critically evaluate some of the assumptions in the field and highlight issues that we believe should be taken into consideration when interpreting lipid content data in C. elegans.
    Critical Reviews in Biochemistry and Molecular Biology 09/2014; 50(1):1-16. DOI:10.3109/10409238.2014.959890 · 7.71 Impact Factor
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    • "Recently, Craig and Moon [25] examined the potential of zebrafish as a model for understanding energetics and fuel usage; they identified key transcriptomic regulators of liver metabolism related to fasting, particularly the master cellular energy sensor, adenosine monophosphate-activated protein kinase (AMPK). However, the upstream regulators of these pathways are poorly understood, although evidence from studies of mammalian models supports the inhibition of AMPK activity by serotonin, linking serotonergic pathways with energy metabolism [26]. Furthermore, there is evidence that miRNAs may also play a role regulating AMPK activity in dehydration-mediated metabolic depression in Xenopus laevis [27]. "
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    ABSTRACT: This study examined the similarities in microRNA profiles between fasted and fluoxetine (FLX) exposed zebrafish and downstream target transcripts and biological pathways. Using a custom designed microarray targeting 270 zebrafish miRNAs, we identified 9 differentially expressed miRNAs targeting transcripts in biological pathways associated with anabolic metabolism, such as adipogenesis, cholesterol biosynthesis, triacylglycerol synthesis, and insulin signaling. Exposure of female zebrafish to 540 ng/L FLX, an environmentally relevant concentration and a known metabolic repressor, increased specific miRNAs indicating greater inhibition of these pathways in spite of continued feeding. Further examination revealed two specific miRNAs, dre-let-7d and dre-miR-140-5p, were predicted in silico to bind to a primary regulator of metabolism, adenosine monophosphate-activated protein kinase (AMPK), and more specifically the two isoforms of the catalytic subunit, AMPKα1 and α2, respectively. Real-time analysis of the relative transcript abundance of the α1 and α2 mRNAs indicated a significant inverse relationship between specific miRNA and target transcript. This suggests that AMPK-related pathways may be compromised during FLX exposure as a result of increased miRNA abundance. The mechanism by which FLX regulates miRNA abundance is unknown but may be direct at the liver. The serotonin transporter, slc6a4, is the target of FLX and other selective serotonin reuptake inhibitors (SSRI) and it was found to be expressed in the liver, although treatment did not alter expression of this transporter. Exposure to FLX disrupts key hepatic metabolic pathways, which may be indicative of reduced overall fitness and these effects may be linked to specific miRNA abundance. This has important implications for the heath of fish because concentrations of SSRIs in aquatic ecosystems are continually increasing.
    PLoS ONE 04/2014; 9(4):e95351. DOI:10.1371/journal.pone.0095351 · 3.23 Impact Factor
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