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Central and peripheral GLP-1 systems independently suppress eating

Nature Metabolism volume 3, pages 258–273 (2021)Cite this article

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Abstract

The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which, respectively, define the peripheral and central GLP-1 systems. PPG neurons in the nucleus tractus solitarii (NTS) are widely assumed to link the peripheral and central GLP-1 systems in a unified gut–brain satiation circuit. However, direct evidence for this hypothesis is lacking, and the necessary circuitry remains to be demonstrated. Here we show that PPGNTS neurons encode satiation in mice, consistent with vagal signalling of gastrointestinal distension. However, PPGNTS neurons predominantly receive vagal input from oxytocin-receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. PPGNTS neurons are not necessary for eating suppression by GLP-1 receptor agonists, and concurrent PPGNTS neuron activation suppresses eating more potently than semaglutide alone. We conclude that central and peripheral GLP-1 systems suppress eating via independent gut–brain circuits, providing a rationale for pharmacological activation of PPGNTS neurons in combination with GLP-1 receptor agonists as an obesity treatment strategy.

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Fig. 1: PPGNTS neurons selectively encode large meal satiation.
Fig. 2: PPGNTS neurons suppress eating without behavioural disruption.
Fig. 3: Glp1r-expressing VANs suppress eating and condition flavour avoidance.
Fig. 4: Oxtr rather than Glp1r VANs are the major vagal input to PPGNTS neurons.
Fig. 5: PPGNTS neurons are necessary for oxytocin-induced eating suppression.
Fig. 6: PPGNTS neurons are not a major target of AP Glp1r neurons.
Fig. 7: Liraglutide and semaglutide suppress eating independently of PPGNTS neurons.
Fig. 8: PPGNTS neuron activation augments semaglutide-induced eating suppression.

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Data availability

There are no publicly available datasets for this manuscript. All data necessary to interpret, replicate and build on the methods or findings reported here are contained within the manuscript and extended data figures. Primary data from ex vivo calcium recordings, food intake, metabolic and behavioural analyses, videos for BSS coding and photomicrographs for in situ hybridization and immunohistochemistry analyses are available in native format upon request from the corresponding authors. Access to stored tissue samples used for in situ hybridization and immunohistochemistry is available upon request from the corresponding authors. All mouse lines, plasmids and reagents used in this study have been previously published and/or are commercially available, and are detailed in the Reporting Summary. Further information and requests for resources and reagents should be directed to and will be fulfilled by S. Trapp (s.trapp@ucl.ac.uk).

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Acknowledgements

We thank L.B. Knudsen at Novo Nordisk for valuable discussions and provision of liraglutide and semaglutide. We also thank M. Arnold at ETH Zurich and Y. Tan at the University of Florida for their expert technical assistance, and K. Beier at UC Irvine for providing RABV for retrograde tracing. This study was supported by Medical Research Council (MRC) project grant no. MR/N02589X/1 to S.T. The initial collaboration between the Trapp, de Lartigue and Langhans laboratories, which generated this work was made possible thanks to a UCL Global Engagement Fund award to D.I.B., and a UCL Neuroscience ZNZ Collaboration award to S.T. and W.L. Research in the de Lartigue laboratory was funded by the NIH (NIDDK grant no. R01 DK116004) and with institutional support from the University of Florida College of Pharmacy. Research in the Reimann/Gribble laboratories was funded by the Wellcome Trust (grant nos. 106262/Z/14/Z and 106263/Z/14/Z) and the MRC (grant no. MRC_MC_UU_12012/3). Research in the Rinaman laboratory was funded by the US National Institutes of Health (grant nos. MH059911 and DK100685).

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Authors and Affiliations

  1. Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK

    Daniel I. Brierley & Stefan Trapp

  2. Department of Psychology, Program in Neuroscience, Florida State University, Gainesville, FL, USA

    Marie K. Holt & Linda Rinaman

  3. Department of Pharmacodynamics, University of Florida, Gainesville, FL, USA

    Arashdeep Singh, Alan de Araujo, Molly McDougle, Macarena Vergara, Majd H. Afaghani, Karen Scott, Calyn Maske, Eric Krause & Guillaume de Lartigue

  4. Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, USA

    Arashdeep Singh, Alan de Araujo, Molly McDougle, Macarena Vergara, Majd H. Afaghani, Calyn Maske, Eric Krause, Annette de Kloet & Guillaume de Lartigue

  5. Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland

    Shin Jae Lee & Wolfgang Langhans

  6. Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA

    Annette de Kloet

  7. Institute of Metabolic Science, University of Cambridge, Cambridge, UK

    Fiona M. Gribble & Frank Reimann

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Contributions

The concept was developed by D.I.B., M.K.H., W.L., G.L. and S.T. The methodology was designed by D.I.B., M.K.H., F.M.G., F.R., G.L. and S.T. The formal analysis was conducted by D.I.B., A.S. and M.M. The investigation was carried out by D.I.B., M.K.H., A.S., A.A., M.M., M.V., M.H.A., S.J.L., C.M., K.S., G.L. and S.T. Resources were obtained by D.I.B., K.S., W.L., E.K., A.K., F.M.G., F.R., L.R., G.L. and S.T. Data were curated by D.I.B. The original draft was written by D.I.B., G.L. and S.T. Review and editing of the manuscript were conducted by all authors. Visualization was done by D.I.B., M.K.H. and S.T. The work was supervised by D.I.B., K.S., W.L., E.K., A.K., L.R., G.L. and S.T. Project administration was done by D.I.B., G.L. and S.T. Funding was acquired by D.I.B., W.L., F.M.G., F.R., L.R., G.L. and S.T. (contributions are defined according to the CRediT taxonomy).

Corresponding authors

Correspondence to Guillaume de Lartigue or Stefan Trapp.

Ethics declarations

Competing interests

The F.R. and F.M.G. laboratory receives funding from AstraZeneca, Eli Lilly and LGM for unrelated research and F.M.G. consults for Kallyope (New York). All other authors have no competing interests to declare.

Additional information

Peer review information Nature Metabolism thanks David D’Alessio, Kamal Rahmouni and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: George Caputa.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 PPGNTS neurons selectively encode large meal satiation.

a, Experimental model and paradigm for metabolic phenotyping of PPGNTS-DTA mice (DTA, n = 8) or mCherry-transduced controls (mCh, n = 7). n = 8 (DTA) / 7 (mCh) animals for analyses presented in b-o. b, Cumulative hourly food intake over 1 day, 2-way mixed-model ANOVA: Virus F(1,13)=0.015, p = 0.904. c, Daily food intake by sex, 2-way mixed-model ANOVA: Virus F(1,11)=0.012, p = 0.914; Sex F(1,11)=0.683, p = 0.426. d, Directed ambulatory locomotion (excluding fine movements) over 1 day, 2-way mixed-model ANOVA: Virus F(1,11)=0.493, p = 0.497. e-i, Meal pattern and metabolic parameters over 1 day, unpaired 2-tailed t-test or Mann-Whitney U test: (e) U = 25, p = 0.779; (f) t(13)=0.997, p = 0.337; (g) t(13)=0.565, p = 0.582; (h) t(13)=0.797, p = 0.440; (i) t(13)=0.323, p = 0.752. j, Mean bodyweight over the 24 h test period, unpaired 2-tailed t-test: t(13)=0.883, p = 0.393. k,l, Food intake during dark and light phases, unpaired 2-tailed t-test: (k) t(13)=0.668, p = 0.516; (l) t(13)=1.251, p = 0.233. m, 24 h water intake, unpaired 2-tailed t-test: t(13)=0.205, p = 0.841. n, Ensure liquid diet preload intake, unpaired 2-tailed t-test: t(8)=0.219, p = 0.832; and post-Ensure chow intake, Mann-Whitney U test: U = 2, p = 0.038. o, Post-fast refeed intake, unpaired 2-tailed t-test: t(12)=2.501, p = 0.028. p-q, Hourly and cumulative intakes over 1 day from ad libitum eating PPGNTS-hM4Di mice (n = 8 animals), 2-way within-subjects ANOVA: (p) Drug F(1,7)=0.241, p = 0.639; (q) Drug F(1,7)=0.411, p = 0.542. r, Raster plot of chow pellet retrievals during the dark phase. Plots from the same mouse after saline and CNO injections presented adjacently. All data presented as mean ± SEM.

Extended Data Fig. 2 PPGNTS neurons suppress eating without behavioural disruption.

a, Non-cumulative hourly food intake over the circadian cycle from ad libitum eating PPGNTS-hM3Dq mice (n = 7 animals for analyses presented in a-b), 2-way within-subjects ANOVA: Drug x Time F(23,138)=4.599, p < 0.0001. b, Dark phase food intake by sex, 2-way mixed-model ANOVA: Drug F(1,5)=19.97, p = 0.0066; Sex F(1,5)=3.854, p = 0.107. c,d, Photomicrographs of colocalized cFos immunoreactivity and DIO-hM3Dq-mCherry in NTS of PPG-Cre:tdRFP mice perfused 3 hours after injection of saline or CNO (photomicrographs representative of independent experiments from 4/3 animals), cc: central canal. Scale=100 µm (inset 50 µm). e, Proportion of mCherry-expressing neurons co-localised with cFos-ir in mice perfused after administration of saline or CNO (n = 4 (SAL) / 3 (CNO) animals), unpaired 1-tailed t-test: t(5)=13.94, p < 0.0001. f, Non-cumulative hourly food intake over 1 day from 18 h fasted PPGNTS-hM3Dq mice (n = 7 animals for analyses presented in f-h), 2-way within-subjects ANOVA: Drug x Time F(23,138)=3.745, p < 0.0001. The behavioural satiety sequence (BSS) was analysed during the first 40 minutes of the dark phase. g,h, Food intake and eating rate over 40 minute BSS test, paired 2-tailed t-test and Wilcoxon matched pairs test: (g) t(6)=4.088, p = 0.0064; (h) W = 18, p = 0.156. All data presented as mean ± SEM.

Extended Data Fig. 3 Glp1r-expressing VANs suppress eating and condition flavour avoidance.

a–c, Light phase food intake and metabolic parameters from ad libitum eating GLP-1RNodose-hM3Dq mice (n = 7 animals for analyses presented in a-c), paired 2-tailed t-test: (a) t(6)=0.0141, p = 0.989; (b) t(6)=0.952, p = 0.378; (c) t(6)=0.0406, p = 0.969. d, Photomicrographs of cFos immunoreactivity (cFos-ir) in coronal NTS sections from GLP-1R-Cre x PPG-YFP mice bilaterally injected in nodose ganglia with dye (Control) or AAV9-DIO-hM3Dq-mCherry (hM3Dq) and administered saline or CNO (photomicrographs representative of independent experiments from 3/3 animals). Distance in mm posterior to Bregma in bottom left, cc: central canal. Scale=100μm. e, cFos immunoreactive cells in the NTS (mean per section) of control) and hM3Dq mice (n = 3 animals per group for analyses in e-f), unpaired 2-tailed t-test: t(4)=2.981, p = 0.0407. f, PPGNTS neurons colocalised with cFos immunoreactivity in the NTS. Mann-Whitney 2-tailed U-test: U = 0, p = 0.100. g, Photomicrograph of nodose ganglion section from GLP-1R-Cre:tdRFP mouse injected with AAV encoding Cre-dependent channelrhodopsin and eYFP fluorescent reporter (DIO-CHR2-eYFP), and colocalisation of the tdRFP and eYFP reporters (photomicrographs representative of independent experiments from 4 animals). Scale=100 µm. h,i, Quantification of viral transduction specificity (h; co-localised cells as % (±SEM) of all eYFP+ cells) and efficiency (i; colocalised cells as % (±SEM) of all tdRFP+ cells), from a total of 374 tdRFP+ cells and 366 eYFP+ cells from the nodose ganglia of 3 mice. All data presented as mean ± SEM.

Extended Data Fig. 4 Oxtr rather than Glp1r VANs are the major vagal input to PPGNTS neurons.

a, Photomicrograph of coronal NTS section from PPG-Cre:tdRFP mouse transduced with DIO-TVA-mCherry + DIO-RabiesG, and subsequently with rabies virus-ΔG-GFP (RABV). Bilateral NTS injection of TVA + RabiesG and counterbalanced unilateral injection of RABV (4 mice / side) resulted in 40.5% (±5.5) of all PPGNTS neurons being successfully transduced ‘starter’ neurons, identified by colocalisation of mCherry (and/or tdRFP) and GFP (photomicrographs in a-h representative of independent experiments from 8 animals). Despite unilateral RABV injection, starter neurons were observed in left and right NTS in all mice, indicating substantial viral spread and bilateral transduction. Scale=100μm. b, Total RABV + cells in left and right nodose ganglia (LNG / RNG; n = 6 / 7 biologically independent samples), unpaired 2-tailed t-test: t(11)=0.214, p = 0.834. c,d, Quantification of Glp1r and Oxtr colocalisation in nodose ganglia (c), and proportions of dual-expressing Glp1r / Oxtr cells colocalised with RABV (d). This dual population comprises 24.7% of all Glp1r cells and 19.7% of all Oxtr cells. 9% of RABV + vagal inputs to PPGNTS neurons express both Glp1r and Oxtr, and 26.1% of dual-expressing Glp1r / Oxtr cells are RABV + vagal inputs to PPGNTS neurons. e, Quantification of RABV and Glp1r colocalisation in NG as proportions of all RABV + cells and all Glp1r+ cells, including those Glp1r cells that also express Oxtr. f, Quantification of RABV and Oxtr colocalisation in NG as proportions of all RABV + cells and all Oxtr+ cells, including those Oxtr cells that also express Glp1r. g,h, Photomicrographs of left and right nodose ganglion sections showing rabies virus GFP expression (RABV) and Glp1r and Oxtr FISH. RABV + Glp1r colocalisation shown by white arrows, RABV + Oxtr by green arrows and RABV + Glp1r+Oxtr by white-edged green arrow. Scale=100μm. All data presented as mean ± SEM.

Extended Data Fig. 5 PPGNTS neurons are necessary for oxytocin-induced eating suppression.

a,b, Food intake and bodyweight change over 1 day in eGFP and DTA mice (n = 5 (DTA) / 7 (eGFP) animals) administered oxytocin (0.4 mg/kg, i.p.), 2-way mixed-model ANOVA: (a) Drug F(1,10)=0.00474, p = 0.947; (b) Drug F(1,10)=0.0989, p = 0.760. c-d, Photomicrographs of coronal NTS sections from PPG-Cre:GCaMP3 mice injected with eGFP control virus (c) or DTA virus (d). Note the complete absence of green (GCaMP3-expressing, amplified by immunostaining against the GFP antigen) PPGNTS neurons in DTA-ablated tissue, and the extent of viral spread as demonstrated by constitutive expression of mCherry (photomicrographs representative of independent experiments from 7/5 animals). Distance in mm posterior to Bregma in bottom left, cc: central canal. Scale=100μm. All data presented as mean ± SEM.

Extended Data Fig. 6 PPGNTS neurons are not a major synaptic target of area postrema Glp1r neurons.

a, Photomicrographs of coronal NTS section showing RABV expression, Glp1r FISH and TH-ir. RABV + Glp1r+TH-ir colocalisation shown by white-edged green arrows (photomicrographs representative of independent experiments from 4 animals). Scale=100μm (inset 20μm). b,c, Quantification of Glp1r and TH-ir co-localization in area postrema (b), and proportions of dual Glp1r / TH-ir cells co-localised with RABV (c). This dual population comprises 49.4% of all TH-ir cells and 31.2% of all Glp1r cells. 9.7% of RABV + AP inputs to PPGNTS neurons express Glp1r and are TH-ir, and 2.7% of dual Glp1r / TH-ir cells are RABV + AP inputs to PPGNTS neurons. All data presented as mean ± SEM.

Extended Data Fig. 7 Liraglutide and semaglutide suppress eating independently of PPGNTS neurons.

a-e, Cumulative food intake by virus at 1,2,4,6 and 21 hr in eGFP and DTA mice (n = 8 (DTA) / 7 (eGFP) animals for analyses presented in (a-j) administered liraglutide (200 μg/kg, s.c.), 2-way mixed-model ANOVA: (a) Drug F(1,13)=0.246, p = 0.628; (b) Drug F(1,13)=2.108, p = 0.170; (c) Drug F(1,13)=37.44, p < 0.0001, Virus F(1,13)=0.836, p = 0.377; (d) Drug F(1,13)=75.09, p < 0.0001, Virus F(1,13)=1.877, p = 0.194; (e) Drug F(1,13)=154.9, p < 0.0001, Virus F(1,13)=1.272, p = 0.280. f-j, Cumulative food intake by virus at 1,2,4,6 and 21 hr in eGFP and DTA mice administered semaglutide (60 μg/kg, s.c.), 2-way mixed-model ANOVA: (f) Drug F(1,13)=1.965, p = 0.184; (g) Drug F(1,13)=17.1, p = 0.0012; Virus F(1,13)=0.630, p = 0.442; (h) Drug F(1,13)=82.49, p < 0.0001, Virus F(1,13)=0.332, p = 0.574; (i) Drug F(1,13)=98.21, p < 0.0001, Virus F(1,13)=0.840, p = 0.376; (j) Drug F(1,13)=126.1, p < 0.0001, Virus F(1,13)=3.42, p = 0.0873. k-m, Representative photomicrographs of cFos immunoreactivity (cFos-ir) in arcuate nucleus of the hypothalamus (ARC) 4 hours after vehicle (VEH, n = 4 animals) or semaglutide (SEMA, 60 μg/kg, s.c., n = 4 animals) administration, and total cFos count, unpaired 1-tailed t-test: m) t(6)=2.614, p = 0.020. Scale=100μm. (n-p) Representative photomicrographs of cFos-ir in paraventricular nucleus of the hypothalamus (PVN) 4 hours after vehicle or semaglutide administration (n = 4 / 4 animals), and total cFos count, unpaired 1-tailed t-test: (p) t(6)=5.109, p = 0.0011. Scale=100μm. q-t, Representative photomicrographs of cFos-ir in dorsal lateral and external lateral subdivisions of the parabrachial nucleus (dlPBN / elPBN) 4 hours after vehicle or semaglutide administration (n = 3 / 4 animals), and total cFos count, unpaired 1-tailed t-tests: (s) t(5)=1.693, p = 0.0756; (t) t(5)=3.57, p = 0.0080. Semaglutide did not increase cFos-ir in the medial PBN, t(5)=0.435, p = 0.341. Scale=100μm. All data presented as mean ± SEM.

Extended Data Fig. 8 PPGNTS neuron activation augments semaglutide-induced eating suppression.

a-d, Bodyweight change at 24 and 48 hours, and cumulative food intake at 48 and 72 hours (n = 6 animals), 1-way within-subjects ANOVA: (a) Drug F(2.1,10.5)=61.61, p < 0.0001; (b) Drug F(2.3,11.3)=102.7, p < 0.0001; (c) Drug F(2.1,10.6)=24.38, p < 0.0001; (d) Drug F(1.9,9.3)=40.35, p < 0.0001. 72 hr BW data not shown: Drug F(2.0,10.2)=4.22, p = 0.0454, no significant pairwise comparisons. e, Photomicrographs of coronal NTS sections from PPG-Cre:GCaMP3 mice injected with AAV encoding Cre-dependent hM3Dq and mCherry fluorescent reporter (DIO-hM3Dq-mCherry), and colocalisation of the GCaMP3 (amplified by immunostaining against GFP antigen) and mCherry reporters (photomicrographs representative of independent experiments from 4 animals). Distance in mm from Bregma in bottom left, cc: central canal. Scale=100 µm. f,g, Quantification of viral transduction specificity (f; co-localised cells as % (±SEM) of all mCherry+ cells) and efficiency (g; co-localised cells as % (±SEM) of all GCaMP3+ cells), from a total of 410 mCherry+ cells and 391 GCaMP3+ cells from 4 mice. All data presented as mean ± SEM.

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Brierley, D.I., Holt, M.K., Singh, A. et al. Central and peripheral GLP-1 systems independently suppress eating. Nat Metab 3, 258–273 (2021). https://doi.org/10.1038/s42255-021-00344-4

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