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State-dependent central synaptic regulation by GLP-1 is essential for energy homeostasis

Abstract

Central glucagon-like peptide-1 (GLP-1), secreted by a distinct population of nucleus tractus solitarius neurons, suppresses feeding but the exact mechanisms of action in the brain remain unclear. Here, we investigate a descending circuit formed by GLP-1 receptor (GLP-1R) neurons in the paraventricular hypothalamic nucleus (PVNGLP-1R) projecting to the dorsal vagal complex (DVC) of the brain stem in mice. PVNGLP-1R→DVC synapses release glutamate and are augmented by GLP-1. Chemogenetic activation of PVNGLP-1R→DVC suppresses feeding. Under an energy deficit (that is, hunger) state, synaptic strength is weaker but is more profoundly augmented by GLP-1R activation than under energy-replete state. In an obese condition, the dynamic synaptic changes in this circuit are disrupted. Optogenetic activation of PVNGLP-1R→DVC projections suppresses food intake energy state dependently, and blocking its synaptic release or ablating GLP-1Rs in the presynaptic neurons impairs metabolic health. These findings indicate that the state-dependent synaptic regulation by GLP-1 in PVNGLP-1R→DVC descending circuit is important for energy homeostasis.

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Fig. 1: PVNGLP-1R→DVC descending circuit is regulated by GLP-1R-mediated signalling.
Fig. 2: State-dependent PVNGLP-1R→DVC neuronal activity suppresses feeding.
Fig. 3: State-dependent synaptic plasticity of PVNGLP-1R→DVC neurons.
Fig. 4: HFD-DIO blunts the state-dependent synaptic plasticity of PVNGLP-1R→DVC neurons.
Fig. 5: HFD blunts optogenetic activation of the PVNGLP-1R→DVC projection induced feeding suppression.
Fig. 6: Chronic perturbation of PVNGLP-1R→DVC neurons.

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Data availability

The data and datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request. Original histological images are available via figshare at https://doi.org/10.6084/m9.figshare.28602683 (ref. 67).

Code availability

Code used to analyse fibre photometry and open-field data is available via GitHub at https://github.com/RohanSavani/PVN_GLP1R.

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Acknowledgements

We thank H. Kwon for help with the CLAMS assay; A. Tahiri and N. Hammed for help on the ITT and GTT experiments; M. Yang for help with part of the histology and J. Wu for the helpful discussions. This study was supported by grants from the Robert Wood Johnson Foundation to the Child Health Institute of New Jersey (RWJF grant no. 74260, Z.P.P.), NIH grant no. NIMH RF1MH120144 (Z.P.P.), NIH grant no. NIDDK R01DK131452 (Z.P.P.), NIH grant no. NIDDK R01DK122167 (A.E.), startup funding from New York Medical College (A.E.), grant no. CIHR PJT 180576 (M.B.W.), grant no. NSERC 72067156 (M.B.W.) NIH grant no. NIDDK R01DK136641 (M.A.R.) and the Whitehall Foundation grant (no. 2022-12-051, M.A.R.). L.W. was supported by the New Jersey Governor’s Council for Medical Research and Treatment of Autism Postdoctoral Fellowship (grant no. CAUT24DFP) and the NExT-Metabolism Pilot Award (grant no. 500301). I.S. was supported by an NSERC/CREATE fellowship.

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Authors and Affiliations

Authors

Contributions

L.W. conducted animal surgery, electrophysiology and animal behaviour experiments. R.H.S. conducted fibre photometry recording, data analysis and animal behaviour analysis. Y.L. conducted part of the animal surgery. M.B. conducted part of the electrophysiology recording. J.L.-I. conducted part of the animal behaviour experiments. E.P. conducted part of the histology and analysis. I.S. conducted part of the analysis. W.X. provided the AAV for expressing AAV-CMV-fDIO-TeNT-EYFP and AAV-DIO-SynaptoTag2. A.E., M.B.W., H.J.G. and M.A.R. provided conceptual input on experimental design. Z.P.P. and L.W. conceived the project, designed the experiments, and wrote the paper with input from all authors.

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Correspondence to Zhiping P. Pang.

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Nature Metabolism thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Revati Dewal, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 PVNGLP-1R neurons project to different downstream targets.

a. Experimental paradigm for tracing PVNGLP-1R neuronal outputs using AAV-mediated Cre-dependent expression of SynaptoTag2. The bicistronic expression cassette expresses cell-filling mCherry and a synapse-specific EGFP-synaptobrevin-2 fusion protein (EGFP-Syb2). b. Representative images of the PVN and downstream targets of PVNGLP-1R neurons in the brain of GLP-1R-ires-Cre mice with AAV-SynaptoTag2 injected into the PVN. c. Quantifications of downstream targets of PVNGLP-1R neurons in the brain. EGFP-Syb2 signal is normalized to the fluorescence intensity of the PVH (n = 4 mice). d. Experimental paradigm for retrograde tracing of DVC inputs from the GLP-1R expressing neurons. AAVrg-DIO-EYFP was injected into the DVC in GLP-1R-ires-Cre mice. e. Representative image of retrogradely labeled PVNGLP-1R →DVC neurons. f. Quantification of PVNGLP-1R→DVC neurons along the anterior to posterior axis (n = 3 mice). Data are presented as mean ± SEM. 3 V: the third ventricle; cc: central canal; scp: superior cerebellar peduncle.

Source data

Extended Data Fig. 2 PVNGLP-1R→DVC neurons do not have apparent collateral projections.

a. Experimental paradigm using AAVrg-DIO-Flpo and AAV-fDIO-EYFP to trace PVNGLP-1R →DVC neuronal projections. b. Representative images of PVNGLP-1R →DVC neurons using the strategy depicted in (a).(n = 3 mice) c. Experimental paradigm for dual-color retrograde tracing using AAVrg-DIO-EYFP injected into the DVC and AAVrg-DIO-tdTomato into the LPBN of GLP-1R-ires-Cre mouse. d. Images showing retrogradely labeled PVNGLP-1R neurons using the strategy depicted in (c) (n = 1 mouse). e. Experimental paradigm for dual-color retrograde tracing using AAVrg-DIO-EYFP into the DVC region and AAVrg-DIO-tdTomato into the LC region in GLP-1R-ires-Cre mouse. f. Images showing retrogradely labeled PVNGLP-1R neurons via the strategy depicted in (e) (n = 1 mouse).

Extended Data Fig. 3 GLP-1R mediated signaling enhances DVC neuron synaptic inputs.

a. Representative image of a recorded DVC neuron labeled with neurobiotin. DMV neurons were visualized with ChAT immunostaining (n > 3 mice). b. Representative traces of sEPSCs with or without Exn-4 (100 nM). c. Pooled data of frequency and amplitude of sEPSCs recorded in DVC neurons (frequency: two-tailed Wilcoxon matched-pairs signed rank test, p < 0.0001; amplitude: two-tailed Wilcoxon matched-pairs signed rank test, p = 0.5876; n = 35 cells/12 mice). d. The vast majority of DMV preganglionic motor neurons (ChAT-positive) do not express GLP-1R. GLP-1R-expressing neurons are visualized via ChR2-EYFP expression. e. Enlarged view of the area shown in panel d. n = 3 mice. f. Quantification of AMPAR-mediated synchronous oEPSC (that is, first peak) amplitudes before and after Exn-4 application with 5 mM Sr2+in external ACSF (two-tailed paired t-test, t(10) = 2.935, p = 0.0166, n = 10 cells/3 mice). Note that these traces are the same from Fig. 1n, but to emphasize the synchronous release phase for quantifications. Data are presented as mean ± SEM. p < 0.05; p < 0.0001.

Source data

Extended Data Fig. 4 Chemogenetic activation of PVNGLP-1R→DVC neurons via hM3Dq suppresses food intake.

a. Food intake consumption after i.p. saline injection (control) in GLP1R-ires-Cre mice expressing hM3Dq- or control-virus in PVNGLP-1R→DVC neurons during the dark cycle (related to Fig. 2e) (two-way ANOVA, Group effect: F(1, 14) = 2.492, p = 0.1368; Time effect: F(3, 42) = 89.98, p < 0.0001; interaction: F(3, 42) = 0.6374, p = 0.5952, control n = 9 mice, hM3Dq n = 7 mice). b. Food intake upon activation of PVNGLP-1R→DVC neurons in a fasted-refeeding paradigm during the light cycle (two-way ANOVA, main effect of Group: F(1, 14) = 10.83, p = 0.0054; main effect of Time: F(1.570, 21.98) = 60.54, p < 0.0001; interaction between Group and Time: F(3, 42) = 1.921, p = 0.1408; Sidak’s multiple comparisons test vs. control: 30 min p = 0.0056; 60 min p = 0.0188; 120 min p = 0.0296; 180 min p = 0.0346; control n = 9 mice, hM3Dq n = 7 mice). c. Food intake consumption upon activation of PVNGLP-1R→DVC neurons in the fed light cycle (two-way ANOVA, Group effect: F(1, 14) = 6.781, p = 0.0208; Time effect: F(1.903, 26.64) = 21, p < 0.0001; interaction: F(3, 42) = 3.899, p = 0.0152; Sidak’s multiple comparisons test vs. control: 30 min p = 0.063; 60 min p = 0.2495; 120 min p = 0.0623; 180 min p = 0.0256; control n = 9 mice, hM3Dq n = 7 mice). d. Glucose tolerance test with or without chemogenetic activation (two-way ANOVA, Group effect: F(1, 14) = 1.663, p = 0.2181; Time effect: F(2.740, 38.36) = 355.1, p < 0.0001; interaction: F(4, 56) = 1.342, p = 0.2659; control n = 9 mice, hM3Dq n = 7 mice). e. Representative traces of animal exploration in the open field with or without chemogenetic activation of PVNGLP-1R→DVC neurons. f. Time spent in the center of the open field (two-tailed t-test, t (16) = 1.617, p = 0.1282; control n = 9 mice, hM3Dq n = 7 mice). g. Total traveled distance in the open field (two-tailed t-test, t(16) = 1.283, p = 0.2205; control n = 9 mice, hM3Dq n = 7 mice). h. Quantification of light-dark box assay for anxiety-like behaviors: time spent in the dark zone (two-tailed t-test, t(16) = 0.1509, p = 0.8822; control n = 9 mice, hM3Dq n = 7 mice). i. Dark zone entries (two-tailed t-test, t(16) = 0.0516, p = 0.9596; control n = 9 mice, hM3Dq n = 7 mice). Data are presented as mean ± standard error of the mean (SEM). p < 0.05; p < 0.01.

Source data

Extended Data Fig. 5 Fiber Photometry measurement of PVNGLP-1R→DVC neuronal calcium activity in responding to various sensory inputs.

a. Average response of fiber photometry data showing calcium dynamics of PVNGLP-1R→DVC neurons during self-grooming behavior. b. Pooled data (two-tailed paired t-test, t(5) = 2.822, p = 0.0477; n = 5 mice). c. Average response of fiber photometry calcium dynamics of PVNGLP-1R→DVC neurons during tail picking-induced stress d. Pooled data (two-tailed paired t-test, t(5) = 4.109, p = 0.0147; n = 5 mice). e. Heatmap showing calcium dynamics of PVNGLP-1R→DVC neurons during different food/object tea ball drop stimuli across different energy states. f. Quantitation of the areas under the curve (AUC) of calcium response (one-way ANOVA, F(3,16) = 4.383, p = 0.0197, n = 5 mice). Data are presented as mean ± SEM. p < 0.05.

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Extended Data Fig. 6 Electrophysiological characterization of PVNGLP-1R→DVC neurons under different energy states.

a. Experimental paradigm. b. Intrinsic electrophysiological characterization of PVNGLP-1R→DVC neurons. Summary of capacitance (two-tailed t-test, t(52) = 0.6357, p = 0.5279; Fed n = 24 cells/3 mice, Fasted n = 28 cells/3 mice). c. Input resistance (two-tailed Mann-Whitney test, p = 0.7134; Fed n = 24 cells/3 mice, Fasted n = 28 cells/3 mice). d. Resting membrane potential (two-tailed Mann-Whitney test, p = 0.0049; Fed n = 24 cells/3 mice, Fasted n = 28 cells/3 mice). e. Representative traces of spontaneous action potentials (sAPs). f. Quantification of sAP frequency (two-tailed Mann-Whitney test, p = 0.3148; Fed n = 24 cells/3 mice, Fasted n = 28 cells/3 mice). g. Representative traces of neurons responding to ramping current injection. Insert show the current injection protocol. h. Quantification of ramping current injection action potential firing number (two-tailed Mann-Whitney test, p = 0.3461; Fed n = 25 cells/3 mice, Fasted n = 27 cells/3 mice). i, Representative traces of neurons in response to stepped current injection. Insert shows the current injection protocol. j. Plot of the number of APs as a function of injected current (two-way ANOVA, Group effect: F(1, 48) = 0.7961, p = 0.3767; Time effect: F(1.340, 64.33) = 98.47, p < 0.0001; interaction: F(5, 240) = 0.3641, p = 0.8728; Fed n = 24 cells/3 mice, Fasted n = 26 cells/3 mice). Data are presented as mean ± SEM. p < 0.01.

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Extended Data Fig. 7 Electrophysiological characterization of PVNGLP-1R→DVC neurons in HFD-induced obesity animals.

a. Experimental paradigm. b. Body weight of control and HFD-induced obese animals (two-tailed t-test, t (11) = 4.671, p = 0.0012; control n = 5 mice, HFD n = 6 mice). c. Intrinsic electrophysiological characterization of PVNGLP-1R→DVC neurons. Summary of capacitance (c) (two-tailed Mann-Whitney test, p = 0.2638; control n = 20 cells/3 mice, HFD n = 32 cells/3 mice). d. Resting membrane potential (RMP) (two-tailed t-test, t (51) = 3.212, p = 0.0023; control n = 20 cells/3 mice, HFD n = 31 cells/3 mice). e. Representative traces of spontaneous action potentials (sAPs). f. Pooled data of sAP frequency (two-tailed t-test, t (20) = 2.042, p = 0.0561; control n = 6 cells/3 mice, HFD n = 14 cells/3 mice). g. Representative traces of neurons in response to ramp current injection. Inset shows the current injection protocol. h. Quantification plot of ramping current injection-induced AP firing number (two-tailed Mann-Whitney test, p = 0.5784; control n = 20 cells/3 mice, HFD n = 30 cells/3 mice). i. Representative traces of neurons in response to stepped current injection. Inset shows the current injection protocol. j. Plot of the number of APs as a function of injected current (two-way ANOVA, Group effect: F(1, 48) = 0.1073, p = 0.7447; Time effect: F(1.362, 64.97) = 157.7, p < 0.0001; interaction: F(10, 477) = 0.7476, p = 0.6795; control n = 20 cells/3 mice, HFD n = 30 cells/3 mice). Data are presented as mean ± SEM. p < 0.01.

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Extended Data Fig. 8 Liraglutide augments PVNGLP-1R→DVC synaptic release in HFD-fed mice.

a. Representative traces of AMPAR-oEPSCs and NMDAR oEPSCs in HFD-fed mice with or without i.p. injection of 400 µg/kg liraglutide. b. Pooled data of NMDAR-oEPSCs (two-tailed t-test, t (43) = 2.561, p = 0.0153; HFD n = 18 cells/3 mice, Liraglutide n = 25 cells/3 mice). c. AMPAR/NMDAR oEPSCs ratio (two-tailed t-test, t(43) = 1.391, p = 0.1718; HFD n = 18 cells/3 mice, Liraglutide n = 18 cells/3 mice). Data are presented as mean ± SEM. p < 0.05.

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Extended Data Fig. 9 Impact of optogenetic activation of PVNGLP-1R projections in the DVC on food intake and aversion.

a. Quantification of fasted-refeeding normalized chow intake for ChR2/EYFP mice (normalized to EYFP/ChR2 off average chow intake, 470 nm 20 Hz, 1 s on, 0.5 s off; two-tailed Mann-Whitney test, p = 0.0146, EYFP n = 6 mice, ChR2 n = 7 mice). b. Experimental paradigm for testing sucrose licking in mouse in a head-fixed format. Animals were injected with AAV-ChR2 or EYFP into the PVN, and fiber optics were implanted in the DVC. c. Quantification of body weight changes after 12 weeks of HFD-DIO (two-tailed paired t-test, t(13) = 4.257, p = 0.0011; EYFP n = 6 mice, ChR2 n = 7 mice). d. Raster plots of licks (consumption of 10% sucrose) of energy-replete (fed) ChR2 and EYFP mice (post 12 weeks HFD) after pre (5 min), during blue light photostimulation (470 nm 20 Hz, 1 s on, 0.5 s off, 5 min), and 5 min post optogenetic stimulation. e. Normalized sucrose licking rates before, during and after optogenetic activation (two-way ANOVA, Group effect: F (3, 22) = 1.335e + 017, p < 0.0001; Time effect: F (1.294, 28.47) = 13.27, p = 0.0005; interaction between Group and Time: F (6, 44) = 0.5878, p = 0.7381; Sidak’s multiple comparisons test vs. EYFP Light On ChR2 p = 0.0003; EYFP n = 6 mice, ChR2 n = 7 mice). f. Representative heatmaps depicting the time spent in the real-time place preference task. The colorbar denotes time spent in an area normalized to the maximum time spent. g. Preference of EYFP and ChR2 mice for the photostimulation chamber (470 nm, 20 Hz) (two-tailed Mann-Whitney test, p = 0.9452; EYFP n = 6 mice, ChR2 n = 7 mice). Data are presented as mean ± SEM. p < 0.05; p < 0.01; p < 0.001. Illustration in b adapted from SciDraw under a Creative Commons license CC BY 4.0.

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Extended Data Fig. 10 Comprehensive metabolic analyses of animals after inactivation of PVNGLP-1R→DVC synaptic release and daily food consumption.

a. Energy expenditure (EE) (two-way ANOVA, the main effect of Group: F(1, 14) = 0.01004, p = 0.9216; main effect of Time: F(6.449, 90.29) = 4.545, p = 0.0003; interaction between Group and Time: F(159, 2226) = 1.054, p = 0.3132; control n = 7 mice, TeNT n = 9 mice). b. The volume of carbon dioxide produced (VCO2) (two-way ANOVA, the main effect of Group: F(1, 14) = 0.1053, p = 0.7503; main effect of Time: F (6.291, 88.08) = 4.765, p = 0.0002; interaction between Group and Time: F(159, 2226) = 0.9634, p = 0.6126; control n = 7 mice, TeNT n = 9 mice). c. Respiratory exchange ratio (RER) (two-way ANOVA, Group effect: F (1, 14) = 4.844, p = 0.0450; Time effect: F(3.463, 48.49) = 2.22, p = 0.0893; interaction: F (159, 2226) = 0.442, p > 0.9999; control n = 7 mice, TeNT n = 9 mice). d. Oxygen consumed (VO2) (two-way ANOVA, Group effect: F(1, 14) = 0.003172, p = 0.9559; Time effect: F(6.303, 88.25) = 3.659, p = 0.0023; interaction: F(119, 1666) = 1.157, p = 0.1256; control n = 7 mice, TeNT n = 9 mice). e. Average locomotor activity of TeNT and control (GFP) animals (two-way ANOVA, Group effect: F(1, 12) = 1.862, p = 0.1974; Time effect: F(8.698, 104.4) = 2.654, p = 0.0089; interaction between Group and Time: F(159, 1908) = 1.101, p = 0.1919; control n = 6 mice, TeNT n = 8 mice). f. Experimental paradigm for inactivating PVNGLP-1R→DVC synaptic release. Cre-dependent expression of Flpo and Flpo-dependent expression of TeNT in PVNGLP-1R →DVC neurons. g. Average daily food intake of EYPF HFD-fed obese animals’ baseline for 2 days and after i.p. injection of 200 μg/kg liraglutide for 5 days (two-tailed paired t-test, t(7) = 4.658, p = 0.0035; EYFP n = 7 mice). h. Average daily food intake consumption of TeNT HFD-fed obese animals’ baseline for 2 days and after i.p. injection of 200 μg/kg liraglutide for 5 days (two-tailed paired t-test, t(7) = 5.595, p = 0.0014; TeNT n = 7 mice). Data are presented as mean ± SEM. p < 0.01.

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Wang, L., Savani, R.H., Lu, Y. et al. State-dependent central synaptic regulation by GLP-1 is essential for energy homeostasis. Nat Metab 7, 1443–1458 (2025). https://doi.org/10.1038/s42255-025-01305-x

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