Abstract
Antipsychotic drugs have severe metabolic side effects. Acute use can induce hypothermia, while chronic use often leads to weight gain and associated disorders. However, no treatment is currently available for drug-induced hypothermia, and weight control measures lack evidence for long-term effectiveness. Here we demonstrate that a glucagon-like peptide 2 analogue, teduglutide, effectively prevents olanzapine-induced hypothermia and weight gain, and restores glucose tolerance and insulin sensitivity in mice. Mechanistically, olanzapine suppresses prodynorphin-expressing neurons in the ventromedial hypothalamus (VMHPdyn neurons) via serotonin receptor 2C, while teduglutide activates the same neuron population. Selective ablation of VMHPdyn neurons mimics olanzapine-induced side effects. More importantly, chemogenetic activation of VMHPdyn neurons abolishes olanzapine-induced hypothermia and excessive weight gain, although the psychotropic effects remain intact. Together, our data show that VMHPdyn neurons are the crucial mediator of antipsychotic-induced metabolic dysfunction and glucagon-like peptide 2 receptor agonism may be an effective target to mitigate both acute and chronic side effects.
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Acknowledgements
This work was supported by National Science and Technology Innovation 2030 grants (grant nos. 2022ZD0206100 and 2024YFA1802702 to Z.Z.), National Natural Science Foundation of China grants (grant nos. U23A20433 and 32071010 to Z.Z., grants nos. 32330043, 32192414 and 32192410 to J.H., grant no. 82372583 to S.P., grant no. 82430042 to Y.P. and grant no. 32100799 to H.C.), the Lingang Laboratory (grant no. LG-QS-202203-09 to Z.Z.), Space Medical Experiment Project of CMSP (grant no. HYZHXMN0100 to Z.Z.), the China Postdoctoral Science Foundation (grant nos. 2020TQ0332 and 2020M681415 to Z.Z.), Shanghai Natural Science Foundation (grant no. 22ZR1453900 to Y.P.) and Shanghai Rising star programme (grant no. 21QA1408000 to S.P.). This work was supported by Shanghai Clinical Research and Trail Center and by Shanghai Frontiers Science Center for Bomacromolecules and Precision Medicine.
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Z.Z., J.H. and Y.P. initiated the study, designed experiments and prepared the paper. Y.P. performed most of the experiments. C.F. and Q.Z. conducted the FISH experiments and imaging of the slices. S.P. performed electrophysiology experiments, image layout and diagram drafting. Z.J. and X.X. conducted fMOST imaging and analysed the data. H.C. conducted the single-nucleus RNA sequencing data analysis. S.H. provided administrative support and experimental animals of the study. Y.W. and P.T. wrote MATLAB scripts for fibre photometry experiments and analysed data. X.S. performed LC–MS. Y.F. provided support for the animal model. Z.Z. supervised the study.
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Extended data
Extended Data Fig. 1 AATPs suppress the activity of VMHPdyn neurons.
a, b, Mean traces of core (a) and BAT (b) temperature after acute injection of vehicle or Olz (2.5 mg/kg) in male C57BL/6 mice (N = 3 mice for veh group, N = 4 mice for olz group). c, Atypical antipsychotics and their affinities for Htr2c, from https://www.bindingdb.org/ and https://go.drugbank.com. d–i, Mean VMHPdyn GCaMP fluorescence trace during the indicated AATPs treatment. Risperidone (1.5 mg/kg) (d), Clozapine (10 mg/kg) (e), quetiapine (20 mg/kg) (f), aripiprazole (0.5 mg/kg) (g), amisulpride (50 mg/kg) (h), lurasidone (2 mg/kg) (i) (N = 3-4 mice per group). Data are plotted as mean ± SEM. j, Violin plots showing Htr2c, Drd2, Mc4r, Htr2a, Htr2b, Glp1r, and Glp2r expression distributions in Pdyn-expressing clusters, with male and female plotted separately. P values were determined by Two-way ANOVA followed by Sidak’s multiple-comparison tests in a, b. Shaded area indicated time points that are statistically significant compared to vehicle group.
Extended Data Fig. 2 Systemic injection of Teduglutide enters VMH region in vivo.
Representative images of the hypothalamus showing VMH region labeled by DAPI (blue) and cy3-teduglutide (white), 30 mins after injection of saline or teduglutide (1 mg/kg). Right panels showed zoomed images from the red box labeled in the VMH region in the left panel. Scale bar in the left panel, 100 μm; in the right panel, 10 μm. The experiment was replicated in three mice.
Extended Data Fig. 3 Knockdown of HTR2c in VMHPdyn neurons prevents Olanzapine-induced overweight in female mice.
a, Raw traces and statistical analysis of the effect of CP809101 (50 µM) on VMHPdyn neurons. The statistical analysis illustrates the inter-spike intervals (ISIs) and firing rate change following bath application of CP809101(N = 5 neurons from 4 mice per group). b, Representative traces of the neuronal firing change in the presence (upper) and absence of CP809101 (below) while treated with olanzapine (N = 9 cells from 7 mice per group). c, Quantification (right) of the neuronal firing change (N = 9 cells from 7 mice per group). d, Relative expression level of HTR2c gene in VMH (normalized to GAPDH). e, Change in body weight. f, Change in body composition. g, Changes in blood glucose (left) and the area under the curve (AUC) (right) of mice subjected to ipGTT. h, Changes in blood glucose (left) and AUC (right) of mice subjected to ipITT. i–l, Metabolic cage analysis of food intake (i), physical activity (j), heat production (k) and RER (l). N = 5 mice per group for d–l. Data are plotted as mean ± SEM. P values were determined by Unpaired two-tailed Student’s t-tests in a, d, g(right), h(right), Two-way ANOVA followed by Sidak’s multiple-comparison tests in e, f, g(left), h(left), i–l, followed by Tukey’s multiple-comparison tests in c.
Extended Data Fig. 4 Homogenous function of VMHPdyn neurons with different projections.
a, We searched a published dataset (https://mouse.digital-brain.cn/projectome/hy) and found 241 VMH Pdyn+ neurons. We manually picked 172 neurons whose somata located in the dorsomedial part of the VMH for further analyses. b, We clustered these 172 dmVMH Pdyn+ neurons into 3 projectome-defined subtypes using the algorithm previously described. (Left) The total axon projections of neurons in each subtype were plotted in a 3D mouse brain space. Colors were randomly assigned to each neuron. (Right) A summary of axon projection length (in μm) for each subtype, in each brain area. Each tick represents the axon projection length of a single neuron in each brain area in a heatmap fashion with the scale shown above. c, A dot plot showing the preferred target brain area (column) for each subtype (row). The dot circle’s size and color intensity indicate the percentage of neurons in each subtype that projected to the indicated brain area and the average projection length (in μm) in a heatmap fashion, respectively, with the scale on the right. d, Soma distribution of the 3 subtypes of neurons along the anterior-posterior (AP), dorsal-ventral (DV), and lateral-medial (ML) axis of the Allen mouse brain common coordinate frame (CCFv3). e, Schematics for laser stimulation of VMHpdyn neurons→VLPO projections (left) and a representative brain slice of the fluorescent signals in VMHpdyn neurons→VLPO projections expressing AAV-DIO-SSFO-eYFP (right). White lines indicate the boundaries of brain structures or optic fibers. Scale bar, 200 μm. f–h, Average traces of food intake (f), core (g) and BAT (h) temperature after optogenetic activation of VMHpdyn neurons→VLPO projections. (f–h, N = 3 mice per group). i, Schematics for laser stimulation of VMHpdyn → PAG projections (left) and a representative brain slice of the fluorescent signals in VMHpdyn neurons →PAG projections expressing AAV-DIO-SSFO-eYFP (right). Scale bar, 200 μm. j–l, Average traces of food intake (j), core (k) and BAT (l) temperature after optogenetic activation of VMHpdyn neurons →PAG projections (j–l, N = 3 mice per group). m, Schematics for laser stimulation of VMHpdyn neurons →MEA projections (left) and a representative brain slice of the fluorescent signals in VMHpdyn neurons →MEA projections expressing AAV-DIO-SSFO-eYFP (right). Scale bar, 200 μm. n–p, Average traces of food intake (n), core (o) and BAT (p) temperature after optogenetic activation of VMHpdyn → MEA projections (n–p, N = 3 mice per group). Blue arrows and dotted lines indicate the time of 5 Hz 15-second laser stimulation. e–p, plots data from female mice. See Extended Data Fig. 5 for results from male mice. Shaded area of the graph(e–p) indicated time points that are statistically significant as compared to eYFP group. Data are represented as mean ± SEM. P values were determined by Two-way ANOVA followed by Sidak’s multiple-comparison tests in f–h, j–l, n–p.
Extended Data Fig. 5 Homogenous function of VMHPdyn neurons with different projections in male mice.
a, Schematics for laser stimulation of VMHpdyn → VLPO projections. White lines indicate the boundaries of brain structures. (b–d) Average traces of food intake (b), core (c) and BAT (d) temperature after optogenetic activation of VMHpdyn → VLPO projections. (b–d, N = 3 mice per group). Blue lines indicate the time of 5 Hz 15-second laser stimulation. Data are plotted as mean ± SEM. e, Schematics for laser stimulation of VMHpdyn → PAG projections. White lines indicate the boundaries of brain structures. f–h, Average traces of food intake (f), core (g) and BAT (h) temperature after optogenetic activation of VMHpdyn → PAG projections. (f–h, N = 3 mice per group). Blue lines indicate the time of 5 Hz 15-second laser stimulation. Data are plotted as mean ± SEM. i, Schematics for laser stimulation of VMHpdyn → MEA projections. White lines indicate the boundaries of brain structures. Scale bar, 200 mm. j–l, Average traces of food intake (j), core (k) and BAT (l) temperature after optogenetic activation of VMHpdyn → MEA projections. (j–l, N = 3 mice per group). Blue lines indicate the time of 5 Hz 15-second laser stimulation. Data are plotted as mean ± SEM. Shaded area of the graph indicated time points that are statistically different from eYFP group. P values were determined by Two-way ANOVA followed by Sidak’s multiple-comparison test in b–d, f–h, j–l.
Extended Data Fig. 6 Ablation of VMHPdyn neurons mimicked Olanzapine-induced overweight in male mice.
a, Schematics for the strategy of VMHPdyn neuron ablation and timeline for the experiment. b, changes in Body weight. c, changes in Body composition. d, Changes in blood glucose (left) and AUC (right) of mice subjected to ipGTT. e, Changes in blood glucose (left) and AUC (right) of mice subjected to ipITT. (f–l), Metabolic cage analysis of food intake (f), physical activity (g), heat production (h) and RER (i). for b–i, N = 3 mice per group. b–i, plot data for male mice. j, Schematic representation of the intracerebral (i.c.) olanzapine administration strategy and the experimental timeline. k, changes in body weight. l, changes in food consumption. m, Changes in blood glucose (left) and AUC (right) of mice subjected to ipGTT. n, Changes in blood glucose (left) and AUC (right) of mice subjected to ipITT. j–n, plot data for female mice. for k–n, N = 4 mice per group. Data are plotted as mean ± SEM. P values were determined by Two-way ANOVA followed by Sidak’s multiple-comparison test in b, c, d (left), e (left), k, m (left), n (left) f–i or unpaired two-tailed Student’s t-test in d (right), e (right), l, m (right), n (right).
Extended Data Fig. 7 Chronic olanzapine treatment alters energy homeostasis in C57BL/6 mice.
a, A schematic representation of the experiment. b, changes in Body weight. c, changes in Body composition. d, Changes in blood glucose (left) and AUC (right) of mice subjected to ipGTT. e, Changes in blood glucose (left) and AUC (right) of mice subjected to ipITT. b–e, N = 6 mice per group. f–i, Metabolic cage analysis of food intake (f), physical activity (g), heat production (h) and RER (i). a–i, plot data for female mice; f–i, N = 5 mice per group. j, A schematic representation of the experiment. k, changes in Body weight. l, changes in Body composition. m, Changes in blood glucose (left) and AUC (right) of mice subjected to ipGTT. n, Changes in blood glucose (left) and AUC (right) of mice subjected to ipITT. k–n, N = 6 mice per group. o–r, Metabolic cage analysis of food intake (o), physical activity (p), heat production (q) and RER (r). j–r, plot data for male mice; o–r, N = 5 mice per group. Results are shown as mean ± SEM. P values were determined by Two-way ANOVA followed by Sidak’s multiple-comparison tests in b, c, d (left), e(left), f–i, k, l, m (left), n (left), o–r, or Unpaired two-tailed Student’s t-tests in d (right), e (right), m (right), n (right).
Extended Data Fig. 8 Activating VMHPdyn neurons prevents Olanzapine-induced overweight in male mice.
a, Schematics for the chronic activating of VMHPdyn neurons and timeline for the experiment. b, changes in Body weight. c, Changes in blood glucose (left) and AUC (right) of mice subjected to ipGTT. d, Changes in blood glucose (left) and AUC (right) of mice subjected to ipITT. P values labelled on b, c (left), d (left), are for hM3d-saline group compared to hM3d-CNO group. (e–h) Metabolic cage analysis of food intake (e), physical activity (f), heat production (g) and RER (h). b–h, N = 5 mice per group. Data are plotted as mean ± SEM. P values were determined by Two-way ANOVA followed by Tukey’s multiple-comparison test in b, c (left), d (left), e–h, one-way ANOVA with Tukey’s post hoc tests in c (right), d (right).
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Peng, Y., Feng, C., Peng, S. et al. GLP-2 prevents antipsychotics-induced metabolic dysfunction in mice. Nat Metab 7, 730–741 (2025). https://doi.org/10.1038/s42255-025-01252-7
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DOI: https://doi.org/10.1038/s42255-025-01252-7
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