CoChat
Sign Up
Cited by 148Regulation of Appetite and ObesityHypothalamic control of reproductive hormonesPharmacology and Obesity Treatment

GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans

Open access
Kim, Kyu Sik, Park, Joon Seok, Hwang, Eunsang, Park, Min Jung, Shin, Hwa Yun, Lee, Young Hee, Kim, Kyung Min, Gautron, Laurent +13 more·2024·Science
DOI 10.1126/science.adj2537PMC PMC11961025
Open this paper in CoChat — free accountOpen PDF

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are effective antiobesity drugs. However, the precise central mechanisms of GLP-1RAs remain elusive. We administered GLP-1RAs to patients with obesity and observed a heightened sense of preingestive satiation. Analysis of human and mouse brain samples pinpointed GLP-1 receptor (GLP-1R) neurons in the dorsomedial hypothalamus (DMH) as candidates for encoding preingestive satiation. Optogenetic manipulation of DMH GLP-1R neurons caused satiation. Calcium imaging demonstrated that these neurons are actively involved in encoding preingestive satiation. GLP-1RA administration increased the activity of DMH GLP-1R neurons selectively during eating behavior. We further identified that an intricate interplay between DMH GLP-1R neurons and neuropeptide Y/agouti-related peptide neurons of the arcuate nucleus (ARC NPY/AgRP neurons) occurs to regulate food intake. Our findings reveal a hypothalamic mechanism through which GLP-1RAs control preingestive satiation, offering previously unexplored neural targets for obesity and metabolic diseases.

Integrity signals

Registry

Crossref · 10.1126/science.adj2537

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 21 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    GLP-1 receptors are present in the human dorsomedial hypothalamus.

    “GLP-1Rs in the DMH of humans were apparent (Fig. 1G and fig. S1F), consistent with prior findings (18).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Psilopanagioti A, Int. J. Mol. Sci. 23, 14899 (2022). 36499229 PMC9740138 source

      Not checked in the free run.

  • Findingown data

    GLP-1 receptors are expressed in the DMH of GLP-1R-tdTomato reporter mice.

    “We also detected the expression of GLP-1Rs in the DMH of GLP-1R–tdTomato reporter mice (Fig. 1H) (19, 20).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Cork SC, Mol. Metab. 4, 718– 731 (2015). 26500843 PMC4588458 source

      Not checked in the free run.

    • cites [20] Jensen CB, Endocrinology 159, 665– 675 (2018). 29095968 source

      Not checked in the free run.

  • Findingown data

    LepR and GLP-1R coexpression appears specific to the DMH, because these markers are largely separate in ARC, LHA, and PVH.

    “This coexpression appeared to be specific to the DMH, because LepR- and GLP-1R–positive cells were largely distinct in the ARC, lateral hypothalamic area (LHA), and paraventricular nucleus of the hypothalamus (PVH) (fig. S2, B to D and G).”
    Quote in the paperSubstantial claim
  • Findingown data

    In humans with obesity, GLP-1 receptor agonist treatment raises preingestive satiation.

    “We administered GLP-1RAs to patients with obesity and observed a heightened sense of preingestive satiation.”
    • Also stated in: § GLP-1RAs raise human preingestive satiation · plain
      “In the preingestive phase, the satiation index significantly increased after GLP-1RA treatment with respect to baseline compared with control (prospective food ingestion, food reward, and food motivation satiation index; Fig. 1, C to F, and fig. S1, D and E).”
    • Also stated in: § Linking GLP-1RA effects across species · hedged
      “In humans, GLP-1RA treatment increases preingestive satiation, as indicated by heightened satiation indices in the preingestive phase (response to food cues), before food ingestion.”
    Quote in the paperSubstantial claim
  • Findingown data

    A higher satiation index is associated with lower food ingestion.

    “A higher satiation index was significantly associated with lower food ingestion (fig. S1C).”
    Quote in the paperSubstantial claim
  • May combine two claims. 26
  • Classified as probably not a substantial claim. 3

  • May combine two claims.

    Findingown data

    GLP-1RA treatment consistently raises the satiation index across test phases, whereas control scores decline from baseline to preingestion and remain lower than GLP-1RA groups.

    “GLP-1RA treatment resulted in a consistent increase in the satiation index (prospective food ingestion) throughout the test scheme. By contrast, the satiation index gradually decreased from baseline to the preingestion phase in the control group, and the control group always had significantly lower scores than GLP-1RA treatment groups (Fig. 1B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In mouse DMH, cells coexpressing GLP-1R and LepR exist alongside cells expressing only GLP-1R or only LepR.

    “In addition to GLP-1R–only cells and LepR-only cells, cells expressing both GLP-1R and LepR were also observed, indicating cellular heterogeneity (fig. S2, A and E to K).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Ingestion neurons remain inactive during the preingestive phase, become active at ingestion start, and diminish toward ingestion end.

    “Unlike preingestion neurons, ingestion neurons remained inactive during the preingestive phase. They only became active at the ingestion start and diminished toward the ingestion end (fig. S7, E and G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CNO application on slices containing DMH and ARC depolarizes DMHGLP-1R neurons and hyperpolarizes ARCNPY/AgRP neurons.

    “Bath application of clozapine-n-oxide (CNO) on the brain slices containing DMH and ARC regions depolarized DMHGLP−1R neurons and hyperpolarized ARCNPY/AgRP neurons (Fig. 5B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Inhibiting DMHGLP-1R neurons in fed mice increases eating bout duration and number of bouts.

    “We found that inhibiting DMHGLP−1R neurons in fed mice increased the bout duration and number of bouts (fig. S3, A to G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Preingestion neurons surge and remain elevated during the preingestive phase, wane as ingestion begins, and show a transient spike at ingestion end.

    “During the preingestive phase, the activity of preingestion neurons surged and remained elevated, waning as ingestion began (Fig. 3S). Surprisingly, there was a transient spike at the ingestion end.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Activating DMHGLP-1R neurons in open-loop fasted mice decreases feeding bout duration, bout frequency, and overall feeding duration.

    “Activating DMHGLP−1R neurons in an open-loop paradigm of fasted mice significantly decreased feeding bout duration, bout frequency, and overall feeding duration (fig. S3, H to N).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All recorded ARCNPY/AgRP neurons (8/8) show picrotoxin-sensitive inhibitory postsynaptic currents and decreased action potential firing upon photostimulation of GLP-1R terminals in ARC.

    “All ARCNPY/AgRP neurons (8/8 neurons) showed picrotoxin-sensitive inhibitory postsynaptic currents and exhibited a decrease in action potential firing (APF) upon photostimulation of GLP-1R terminals in the ARC (Fig. 5A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Choice probability analysis identifies preingestion neurons (23%) and ingestion neurons (21%).

    “We subsequently identified two neural groups (Fig. 3, P to S): “preingestion neurons” (23%) and “ingestion neurons” (21%).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    DMHGLP-1R neural activity increases more in the fed state than fasted state and more to high-fat diet than chow.

    “Moreover, DMHGLP−1R neural activity increased significantly more during the fed state than during the fasted state and significantly more in response to HFD than chow (fig. S5, S to V).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Absence of food leads to extinction of goal choice, decreased goal-side preference, and diminished DMHGLP-1R neural response.

    “Absence of food led to extinction of choosing the goal, resulting in decreased preference for the goal side, with the DMHGLP−1R neural response diminishing accordingly (Fig. 3L).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    GLP-1RA injection increases mean bout duration and chow eaten, while inhibition of DMHGLP-1R neurons attenuates this effect.

    “As a result, GLP-1RA injection resulted in increased mean bout duration and chow eaten, whereas inhibition of DMHGLP−1R neurons attenuated this effect (Fig. 4, S to V).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    DMHGLP-1R neural activity is higher during the initial bout than the final bout for chow and high-fat diet, and time spent eating correlates with neural activity increase.

    “DMHGLP−1R neural activity during the initial bout was significantly higher than the final bout for both chow and HFD ingestion, and time spent eating was correlated with neural activity increase (fig. S5, W to Y).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Liraglutide suppresses food intake and body weight in control mice, but these effects are diminished when DMHGLP-1R neurons are inhibited, ARCNPY/AgRP neurons are activated, or GLP-1R is deleted in the DMH.

    “Although liraglutide administration suppressed food intake and body weight in control mice, these effects were diminished when DMHGLP−1R neurons were inhibited, ARCNPY/AgRP neurons were activated, or GLP-1R was deleted in the DMH (Fig. 5G and fig. S10F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Inhibiting DMHGLP-1R neurons in fasted mice over 10 minutes increases bout duration and decreases overall bout number.

    “This inhibition increased bout duration, whereas the overall number of bouts decreased (Fig. 2, G to I, and movie S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Chemogenetic activation of DMHGLP-1R neurons decreases food intake, while inhibition increases food intake.

    “Chemogenetic activation using DMHGLP−1R neurons expressing hM3Dq, a Gq-coupled designer receptor exclusively activated by DREADD (designer receptors exclusively activated by designer drugs), or inhibition using DMHGLP−1R neurons expressing hM4Di, a Gi-coupled DREADD, decreased or increased food intake, respectively (Fig. 5D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    GLP-1R antagonist exendin-3 pretreatment or DMH GLP-1R deletion abrogates liraglutide-induced direct activation of DMHGLP-1R neurons.

    “Pre-treatment of GLP-1R antagonist exendin-3 or deletion of GLP-1R in the DMH abrogated liraglutide-induced direct activation of DMHGLP−1R neurons (fig. S10, A to D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Before conditioning, DMHGLP-1R neural activity does not increase at the start of non-food-directed locomotion but increases after ingestion starts.

    “There was no increase in DMHGLP−1R neural activity at the start of non–food-directed locomotion, whereas neural activity increased after the start of ingestion (Fig. 3, E and F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both DMHGLP-1R and DMHLepR neurons are depolarized and show increased action potential firing 24 hours after intraperitoneal liraglutide injection.

    “Furthermore, both DMHGLP−1R and DMHLepR neurons were depolarized and exhibited an increase in APF 24 hours after intraperitoneal liraglutide injection (Fig. 5F and fig. S9B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Activation of DMHGLP-1R neurons encodes negative valence, whereas inhibition does not evoke valence.

    “Activation of DMHGLP−1R neurons was sufficient to encode negative valence, whereas inhibition failed to evoke any valence, suggesting that activation of DMHGLP−1R neurons is aversive.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Inhibiting DMHGLP-1R neurons in fasted mice increases total eating duration and amount consumed, and increases probability of bout duration size.

    “Additionally, we observed a significant increase in both the total duration of eating and the amount of food consumed, coupled with an increased probability of bout duration size (Fig. 2, J to N), demonstrating that DMHGLP−1R neurons are necessary for satiation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Across all trials, GLP-1RA increases peak DMHGLP-1R neural activity and high probability of z-scores.

    “Across all trials, the potentiation by GLP-1RA was unequivocal, with an increase in peak DMHGLP−1R neural activity and an increase of high probability of z-scores (Fig. 4, L to Q).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Similar results occur in female mice, with no sex-based differences.

    “Similar results could be observed in females, that is, there were no sex-based differences (fig. S12, A to N).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    GLP-1R-expressing and LepR-expressing neurons are not identical populations and show heterogeneity.

    “These results demonstrate that GLP-1R–expressing neurons and LepR-expressing neurons are not identical populations, and there is heterogeneity among these GLP-1R– and/or LepR-expressing populations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Results in female mice mirror males, suggesting a similar role for GLP-1RA-induced preingestive satiation across sexes.

    “Results in females mirrored those observed in males (figs. S4, D and E, and S8), suggesting a similar role for GLP-1RA–induced preingestive satiation across sexes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationown data

    GLP-1RA effects on body weight and food intake may be mediated at least in part through the DMHGLP-1R-ARCNPY/AgRP circuit.

    “we hypothesized that the effect of GLP-1RA on body weight and food intake may be mediated at least in part through the DMHGLP−1R-ARCNPY/AgRP neural circuit.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Injection of GLP-1 into the brain suppresses water intake, and DMH lesions produce hypodipsia.

    “Injection of GLP-1 into the brain suppresses water intake, and DMH lesions are known to produce hypodipsia, suggesting a potential role in thirst satiation (25).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Bellinger LL, Bernardis LL, Physiol. Behav. 76, 431– 442 (2002). 12117580 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ARCNPY/AgRP neurons are well known to encode negative valence.

    “inhibiting ARCNPY/AgRP neurons, which are well known to encode negative valence (9, 16).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Brüning JC, Fenselau H, Science 381, eabl7398 (2023). 37769095 source

      Not checked in the free run.

    • cites [16] Berrios J, Nature 595, 695– 700 (2021). 34262177 PMC8522184 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The DMH plays a pivotal role in long-term metabolic regulation including energy expenditure, thermogenesis, and circadian rhythm.

    “The DMH plays a pivotal role in long-term metabolic regulation, including energy expenditure, thermogenesis, and circadian rhythm (27–29).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27] Lee SJ, Mol. Metab. 11, 33– 46 (2018). 29650350 PMC6001878 source

      Not checked in the free run.

    • cites [28] Maejima Y, Nutr. Metab. 18, 58 (2021). PMC8186199 34098999 source

      Not checked in the free run.

    • cites [29] Huang Z, Sci. Adv. 8, eabn5345 (2022). 35675406 PMC9177072 source

      Not checked in the free run.

29 of 29

  • The paper relies on this without support.

    The specific neural pathway that regulates preingestive satiation is not yet identified.

    “However, the specific neural pathway remains unidentified.”

  • The paper relies on this without support.

    The preingestive phase and DMHGLP-1R mechanism observed in mice correspond to the preingestive satiation process in humans.

    “This effect mirrors the increased preingestive activity of DMHGLP−1R neurons in mice during similar preingestive phases.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Several recent studies have provided evidence for roles in physiological and GLP-1RA anti-obesity-medication-mediated eating control for GLP-1R populations in the locus coeruleus, dorsomedial hypothalamus, and lateral septum.

    “While the hypothalamic arcuate nucleus is the convergence region most investigated to date (20, 51, 52), several recent studies have provided evidence for roles in physiological and GLP-1RA AOM-mediated eating control for GLP-1R populations in the locus coeruleus (50), dorsomedial hypothalamus (53), and lateral septum (54) (Fig. 1B).”

    From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [53]

  • The individual necessity of distinct GLP-1R neuron populations for the anorectic and weight loss effects of GLP-1RAs has now been claimed by multiple studies using various loss-of-function approaches in rodents.

    “The individual necessity of distinct GLP-1R neuron populations for the anorectic and weight loss effects of GLP-1RAs has now been claimed by multiple studies using various loss-of-function approaches in rodents (47, 50‐54, 69).”

    From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [53]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Kim, K. S., Park, J. S., Hwang, E., Park, M. J., Shin, H. Y., Lee, Y. H., Kim, K. M., Gautron, L., Godschall, E., Portillo, B., Grose, K., Jung, S.-H., Baek, S. L., Yun, Y. H., Lee, D., Kim, E., Ajwani, J., Yoo, S. H., Güler, A. D., Williams, K. W., & Choi, H. J.
Affiliations
  • Seoul National University (KR)
  • Center for Hypothalamic Research, Department of Internal Medicine, Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA.
  • The University of Texas Southwestern Medical Center (US)
  • University of Virginia (US)
Corresponding author
  • Kim, Kyu Sik
  • Park, Joon Seok
  • Williams, Kevin W.
  • Choi, Hyung Jin
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-07-26
Volume
385
Issue
6707
Pages
438-446
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.adj2537
PMC
PMC11961025
OpenAlex
W4400079376
Semantic Scholar
db1f98301a54e6e900cb46f35fcc302f1f066e3b
Cited by
148
References
48
Citations by year
2026: 58 · 2025: 70 · 2024: 20
FWCI
31.89
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • Seoul National University Open Repository (Seoul National University) (submittedVersion)
Funders
  • National Research Foundation
  • Korea Health Industry Development Institute (HI22C1060)
  • National Research Foundation of Korea (2021R1A6A3A14044733, 2018R1A5A2025964, NRF- 2018R1A5A2025964)
  • National Institutes of Health
  • National Institute of General Medical Sciences (R35GM140854)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119169, R56DK135501, P01DK119130, P30DK127984)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
Keywords
GLP-1 receptor agonists, GLP-1 receptor, dorsomedial hypothalamus, hypothalamic circuits, arcuate nucleus, food intake regulation, obesity, anti-obesity drugs, optogenetic manipulation, calcium imaging
MeSH terms
Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Animals, Arcuate Nucleus of Hypothalamus, Dorsomedial Hypothalamic Nucleus, Eating, Feeding Behavior, Female, Humans, Hypothalamus, Male, Mice, Inbred C57BL, Neurons, Neuropeptide Y, Obesity, Satiation, Mice, Glucagon-Like Peptide 1, Agouti-Related Protein, Optogenetics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review