Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-aversive Suppression of Feeding

Cheng, Wenwen; Gonzalez, Ian E.; Pan, Warren; Tsang, Anthony H.; Adams, Jeffrey; Ndoka, Ermelinda; Gordian, Desiree; Khoury, Basma; Roelofs, Karen J.; Evers, Simon S.; MacKinnon, Andrew; Wu, Shuangcheng; Frikke-Schmidt, Henriette; Flak, Jonathan N.; Trevaskis, James L.; Rhodes, Christopher J.; Fukada, So‐ichiro; Seeley, Randy J.; Sandoval, Darleen A.; Olson, David P.; Blouet, Clémence; Myers, Martin G.

doi:10.1016/j.cmet.2019.12.012

Cited by 83 publications

(108 citation statements)

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“…Of note, NTS leucine did not produce neuronal activation in the parabrachial nucleus (PBN, Fig. 1b), consistent with the lack of conditioned avoidance in response to parenchymal NTS leucine administration in mice (Cheng et al, 2020).…”

Section: Resultssupporting

confidence: 74%

“…Previous work indicates that NTS inputs can modulate the activity of AgRP (Aklan et al, 2020; Cheng et al, 2020), but the neuroanatomical organization of these inputs and the physiological conditions in which they are engaged to modulate feeding remain unclear. To establish that AgRP neurons are synaptically connected to NTS neurons we performed a series of retrograde viral tracing studies.…”

Section: Resultsmentioning

confidence: 99%

“…We previously showed that NTS sensing of the branched-chain amino acid leucine not only modulates the control of meal size but also rapidly suppresses hunger in fasted animals and increases satiety without the production of conditioned taste aversion (Blouet & Schwartz, 2010; Cheng et al, 2020). Here, we used NTS leucine sensing as a functional entry point to investigate ascending neural circuits engaged by NTS neurons to modulate hunger and satiety.…”

Section: Introductionmentioning

confidence: 99%

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Nutrient sensing in the nucleus of the solitary tract mediates non-aversive suppression of feeding via inhibition of AgRP neurons

Tsang

Nuzacci

Darwish

et al. 2020

Preprint

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10The nucleus of the solitary tract (NTS) is emerging as a major site of action for the appetite-suppressive 11 effects of leading pharmacotherapies currently investigated for the treatment of obesity. However, our 12 understanding of how NTS neurons regulate appetite remains incomplete. Here we used NTS nutrient 13 sensing as an entry point to characterize stimulus-defined neuronal ensembles engaged by the NTS to 14 produce physiological satiety. Using activity-dependent expression of genetically-encoded circuit 15 analysis tools, we found that NTS detection of leucine engages NTS prolactin-releasing peptide (PrRP) 16 neurons to inhibit AgRP neurons via a population of leptin-receptor-expressing neurons in the 17 dorsomedial hypothalamus. This circuit is necessary for the anorectic response to NTS leucine, the 18 appetite-suppressive effect of high protein diets, and the long-term control of energy balance. These 19 results extends the integrative capability of AgRP neurons to include brainstem nutrient sensing inputs. 21Keywords: nucleus of the solitary tract, appetite, obesity, AgRP neurons, hypothalamus, PrRP neurons, 22 metabolic diseases, circuit mapping 23 24 52 provides a neuroanatomical basis for the latter (Petrov et al., 1993), which could explain the ability of 53 high doses of the satiation hormones like CCK to recruit aversive circuits (Swerdlow et al., 1983), and/or 54 provide a mechanism for the synergistic feeding suppressive effects produced by the combination of 55 anorectic signals (Bhavsar et al., 1998; Blevins et al., 2009; Blouet & Schwartz, 2012). Addressing this 56 3 question with molecularly-defined circuit analysis tools is difficult because most identified NTS 57 neurochemical subsets are functionally heterogeneous, respond to multiple cues and project widely 58 throughout the neuraxis (D'Agostino et al., 2016; Rinaman, 2010). Instead, it may be possible to better 59 understand the functional organization of NTS feeding-regulatory circuits using functionally-defined 60 circuit mapping, which could be particularly insightful if subsets of NTS neurons are specialized in the 61 transmission of highly specific sensory cues and organized in a similar fashion as gustatory and vagal 62 sensory neurons (Bai et al., 2019; Williams et al., 2016). Applying such a strategy to signals able to 63 produce satiation or satiety without negative consequences may lead to important new understanding 64 of how to pharmacologically suppress appetite without undesirable side effects. 65We previously showed that NTS sensing of the branched-chain amino acid leucine not only 66 modulates the control of meal size but also rapidly suppresses hunger in fasted animals and increases 67 satiety without the production of conditioned taste aversion (Blouet & Schwartz, 2010; Cheng et al., 68 2020). Here, we used NTS leucine sensing as a functional entry point to investigate ascending neural 69 circuits engaged by NTS neurons to modulate hunger and satiety. In these experiments, Leucine is 70 injected into the NTS ...

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Section: Resultssupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nutrient sensing in the nucleus of the solitary tract mediates non-aversive suppression of feeding via inhibition of AgRP neurons

Tsang

Nuzacci

Darwish

et al. 2020

Preprint

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“…We first sought to define the types of stimuli that activate GFRAL neurons. Unlike other hindbrain cells known to modulate food intake (Cheng et al, 2020b(Cheng et al, , 2020aRoman et al, 2016) refeeding following an overnight fast failed to promote the accumulation of FOS-immunoreactivity (-IR) in eGFP-labelled AP GFRAL neurons in GFRAL eGFP mice; neither did treatment with the appetite-suppressing calcitonin receptor (CALCR) agonist, salmon calcitonin (sCT). In contrast, lipopolysaccharide (LPS), liraglutide (a glucagon-like peptide-1 receptor (GLP-1R) agonist), LiCl (which causes GI distress), and GDF-15 promoted FOS-IR in many AP GFRAL cells ( Figure 1E, F).…”

Section: Resultsmentioning

confidence: 96%

Gfral-expressing Neurons Suppress Food Intake via Aversive Pathways

Sabatini

Frikke-Schmidt

Arthurs

et al. 2020

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To determine the function and mechanisms of action for hindbrain neurons that express GFRAL, the receptor for the anorexigenic peptide, GDF-15, we generated Gfral cre and conditional Gfral CreERT mice. While signals of infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons, the artificial activation of Gfral Creexpressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). Additionally, activation of the smaller population of GFRAL neurons captured by the Gfral CreERT allele decreased gastric emptying and produced a CTA without suppressing food intake, suggesting that GFRAL neurons primarily modulate gastric physiology and stimulate aversive responses. GFRAL neurons most strongly innervated the parabrachial nucleus (PBN), where they targeted CGRP-expressing (CGRP PBN ) neurons. Silencing CGRP PBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated, pathophysiologic signals to the aversive suppression of nutrient uptake and absorption.

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“…BNST-PBN vGLUT2 neurons are enriched in Adcyap1 , which encodes the neuropeptide PACAP, previously identified as a major regulator of stress responses in the BNST (Hammack et al, 2009; Roman et al, 2014), including in contexts of addiction and post-traumatic stress disorder (Miles et al, 2018; Ressler et al, 2011). Both BNST-PBN vGAT and BNST-PBN vGLUT2 neurons express calcitonin receptor (Calcr ), recently associated with the regulation of feeding (Cheng et al, 2020; Pan et al, 2018), and nociceptin (Pnoc ), linked to motivated behaviors including feeding (Hardaway et al, 2019; Parker et al, 2019; Toll et al, 2016). We further validated these RNAseq findings by performing fluorescent in-situ hybridization experiments, which revelated co-expression of Tac2, Sstr3 , and Calcr with vGAT and Adcyap1 with vGLUT2 neurons within the BNST ( Figures S2F-S2I ).…”

Section: Resultsmentioning

confidence: 99%

Extended amygdala-parabrachial circuits alter threat assessment to regulate feeding

Bhatti

Pedersen²,

Mulvey³

et al. 2020

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29An animal's evolutionary success depends on the ability to seek and consume foods while 30 avoiding environmental threats. However, how evolutionarily conserved threat detection circuits 31 modulate feeding is unknown. In mammals, feeding and threat assessment are strongly 32 influenced by the parabrachial nucleus (PBN), a structure that responds to threats and inhibits 33 feeding. Here, we report that the PBN receives dense inputs from the bed nucleus of the stria 34 terminalis (BNST), an extended amygdala structure that encodes affective information. Using a 35 series of complementary approaches, we identify opposing BNST-PBN circuits that modulate a 36 genetically-defined population of PBN neurons to control feeding. This previously unrecognized 37 neural circuit integrates threat assessment with the intrinsic drive to eat. 38 39 Keywords: extended amygdala; bed nucleus of the stria terminalis; parabrachial nucleus; 40 feeding; threat assessment; anxiety; motivation 41 Main text: 42 43 Introduction 44All animals must successfully seek and consume food while avoiding environmental 45 threats to survive. The internal state of an animal directly impacts the expression of risky 46 behaviors, such as exploring a dangerous environment to obtain rewards and maintain 47 homeostasis. Animals must adaptively prioritize certain behaviors to appropriately respond to their 48 internal state (Alhadeff et al., 2018; Burnett et al., 2016). While many studies have explored the 49 interaction of metabolic need states with behavior, how mammals integrate affective-threat 50 assessment with internal need states remains largely unknown. 51Several recent reports have found that in mammals, food consumption and threat 52 assessment are heavily influenced by the parabrachial nucleus (PBN), a pontine structure that 53 integrates visceral and sensory information to encode metabolic needs (Campos et al., 2016(Campos et al., , 54 2018 Carter et al., 2013; Essner et al., 2017; Han et al., 2015; Mu et al., 2017; Roman et al., 55 2016; Ryan et al., 2017; Zséli et al., 2016). The amygdala and extended amygdala are 56 evolutionarily conserved brain regions that encode and integrate valence, stress, and threat to 57 alter behavioral states. Anatomical data suggest that the PBN receives input from several regions 58 that may encode affective information, including the bed nucleus of the stria terminalis (BNST), a 59 structure in the extended amygdala (Douglass et al., 2017; Kim et al., 2013; Mazzone et al., 2018; 60 Zséli et al., 2016). However, the neural circuit mechanisms that underlie the integration of an 61 animal's own motivation to eat with internal affective states regarding environmental threats are 62 still unknown. Here, we identified two previously unknown afferents from distinct populations 63 within the BNST to the PBN that underlie the complex integration of threat-assessment and 64 feeding signals to modulate PBN activity and ultimately regulate state-dependent feeding. 65 66 67 Results 68 Anatomical and Molecular...

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Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-aversive Suppression of Feeding

Abstract: Highlights d NTS Calcr mediates food intake suppression but not aversive responses to sCT d Activating NTS Calcr neurons non-aversively suppresses feeding d These neurons act via non-CGRP PBN neurons d These neurons control long-term energy balance, not just short-term feeding

Cited by 83 publications

References 56 publications

Nutrient sensing in the nucleus of the solitary tract mediates non-aversive suppression of feeding via inhibition of AgRP neurons

Nutrient sensing in the nucleus of the solitary tract mediates non-aversive suppression of feeding via inhibition of AgRP neurons

Gfral-expressing Neurons Suppress Food Intake via Aversive Pathways

Extended amygdala-parabrachial circuits alter threat assessment to regulate feeding

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