Leptin receptor–expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice

Cheng, Wenwen; Ndoka, Ermelinda; Hutch, Chelsea R.; Roelofs, Karen J.; MacKinnon, Andrew; Khoury, Basma; Magrisso, Jack; Kim, Ki Suk; Rhodes, Christopher J.; Olson, David P.; Seeley, Randy J.; Sandoval, Darleen A.; Myers, Martin G.

doi:10.1172/jci.insight.134359

Cited by 50 publications

(56 citation statements)

References 38 publications

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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: 97%

Gfral-expressing Neurons Suppress Food Intake via Aversive Pathways

Sabatini

Frikke-Schmidt

Arthurs

et al. 2020

Preprint

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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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Section: Resultsmentioning

confidence: 97%

Gfral-expressing Neurons Suppress Food Intake via Aversive Pathways

Sabatini

Frikke-Schmidt

Arthurs

et al. 2020

Preprint

Self Cite

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“…Alternatively, other neurotransmitters could mediate the effects of LepR neurons, although LepRs do not colocalize with CART (cocaine-and amphetamine-regulated transcript), BDNF, NPY, nesfatin, catecholamines, GABA, PRP (prolactin-releasing peptide), or NOS (nitric oxide synthase; Garfield et al, 2012). Interestingly, LepR neurons have been shown to express CCK mRNA (Garfield et al, 2012), and the activation of NTS CCK neurons inhibits food intake (Roman et al, 2017); although a more recent study did not see colocalization when CCK-eGFP reporter mice were used (Cheng et al, 2020).…”

Section: Role Of Lepr-expressing Neuronsmentioning

confidence: 97%

“…Activation of LepR neurons for 4 d in the NTS suppresses food intake and decreases body weight (Cheng et al, 2020). In addition, these neurons are thought to integrate the response to leptin with forebrain regions as fourth-ventricle, leptin-conjugated saporin decreases the sensitivity to forebrain leptin inhibition of food intake (Harris, 2020).…”

Section: Role Of Lepr-expressing Neuronsmentioning

confidence: 99%

“…Furthermore, GLP1 neurons form local circuits in the NTS, including making connections with each other (Card et al, 2018), and as GLP1 neurons are also glutamatergic they could contribute to some of the polysynaptic circuits onto LepR neurons. However, Cheng et al (2020) recently suggested that LepR neurons suppress food intake independently of GLP1 in mice (Cheng et al, 2020). The actions of leptin in the NTS are increased in mice lacking PTP1B, specifically in POMC neurons (De Jonghe et al, 2012), supporting a role for this population mediating some of the actions of leptin.…”

Section: Role Of Lepr-expressing Neuronsmentioning

confidence: 99%

“…In addition, selective knockdown of LepRs in NTS neurons is associated with hyperphagia, weight gain, and attenuation of responses to satiety signals such as CCK and intraluminal nutrients (Hayes et al, 2010;Kanoski et al, 2012). Furthermore, activation of LepR-expressing neurons inhibits food intake and reduces body weight (Cheng et al, 2020). Together, this suggests that both presynaptic and postsynaptic LepRs at the vagal-NTS synapse are important for the control of food intake, yet the underlying mechanisms by which leptin influences NTS neuronal activity are not well understood.…”

Section: Introductionmentioning

confidence: 99%

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Leptin Sensitizes NTS Neurons to Vagal Input by Increasing Postsynaptic NMDA Receptor Currents

et al. 2020

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Leptin signaling within the nucleus of the solitary tract (NTS) contributes to the control of food intake, and injections of leptin into the NTS reduce meal size and increase the efficacy of vagus-mediated satiation signals. Leptin receptors (LepRs) are expressed by vagal afferents as well as by a population of NTS neurons. However, the electrophysiological properties of LepRexpressing NTS neurons have not been well characterized, and it is unclear how leptin might act on these neurons to reduce food intake. To address this question, we recorded from LepR-expressing neurons in horizontal brain slices containing the NTS from male and female LepR-Cre X Rosa-tdTomato mice. We found that the vast majority of NTS LepR neurons received monosynaptic innervation from vagal afferent fibers and LepR neurons exhibited large synaptic NMDA receptor (NMDAR)mediated currents compared with non-LepR neurons. During high-frequency stimulation of vagal afferents, leptin increased the size of NMDAR-mediated currents, but not AMPAR-mediated currents. Leptin also increased the size of evoked EPSPs and the ability of low-intensity solitary tract stimulation to evoke action potentials in LepR neurons. These effects of leptin were blocked by bath applying a competitive NMDAR antagonist (DCPP-ene) or by an NMDAR channel blocker applied through the recording pipette (MK-801). Last, feeding studies using male rats demonstrate that intra-NTS injections of DCPP-ene attenuate reduction of overnight food intake following intra-NTS leptin injection. Our results suggest that leptin acts in the NTS to reduce food intake by increasing NMDAR-mediated currents, thus enhancing NTS sensitivity to vagal inputs.

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