Abstract
Interoception broadly refers to awareness of one’s internal milieu. Although the importance of the body-to-brain communication that underlies interoception is implicit, the vagal afferent signalling and corresponding brain circuits that shape perception of the viscera are not entirely clear. Here, we use mice to parse neural circuits subserving interoception of the heart and gut. We determine that vagal sensory neurons expressing the oxytocin receptor (Oxtr), referred to as NGOxtr, send projections to cardiovascular or gastrointestinal tissues and exhibit molecular and structural features indicative of mechanosensation. Chemogenetic excitation of NGOxtr decreases food and water consumption, and remarkably, produces a torpor-like phenotype characterized by reductions in cardiac output, body temperature and energy expenditure. Chemogenetic excitation of NGOxtr also creates patterns of brain activity associated with augmented hypothalamic–pituitary–adrenal axis activity and behavioural indices of vigilance. Recurrent excitation of NGOxtr suppresses food intake and lowers body mass, indicating that mechanosensation of the heart and gut can exert enduring effects on energy balance. These findings suggest that the sensation of vascular stretch and gastrointestinal distention may have profound effects on whole-body metabolism and, possibly, mental health.
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Acknowledgements
This project received funding from National Institutes of Health grants HL150750 (to E.G.K), AT012142 (to E.G.K., A.d.K. and G.d.L.), HL136595 (to A.d.K.), AHA 23POST1020034 (to K.E.) and R01DK116004 (to G.d.L.).
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K.A.S., G.d.L., A.D.d.K. and E.G.K. designed the study, analysed the data and wrote the manuscript. D.N.J., R.M.-H. and M.K.K. analysed the data; Y.T. analysed the data and contributed to study design; K.E. analysed the data and assisted with manuscript writing. All authors were involved with the implementation of the study.
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Extended data
Extended Data Fig. 1 Impact of bilateral NG injection of OxtrCre mice with the Cre-inducible AAVPHP.S-FLEX-tdTomato or AAV5-hSyn-DIO-Gq-mCherry on fluorophore expression in the hindbrain.
(a) Representative confocal scans of coronal sections spanning the brainstem of OxtrCre mice that received a bilateral NG injection with the Cre-inducible AAVPHP.S-FLEX-tdTomato. (b) Corresponding atlas schematics of representative coronal sections highlighting the area postrema (AP), nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus (DMNV), and nucleus ambiguous (NA). (c) Representative coronal section depicting tdTomato-labeled fibers in the AP and NTS; however, the DMNV and NA are unlabeled. (d, left) Schematic of bilateral injection of AAVPHP.S-FLEX-tdTomato into the NG. (middle) Representative higher magnification images of the AP, NTS, DMNV, and (right) the NA. (e, left) Schematic of bilateral injection of AAV5-hSyn-DIO-mCherry into the NG. (middle) Representative higher magnification images of the AP, NTS, DMNV, (right) the and NA. CC; Central Canal, 4 V; 4th Ventricle. Scale Bars; 1 mm (a, c), 100 µm (d, e). n = 6-8 sections per 4 mice (tdTom groups) and 2-3 sections per 5 mice (Gq-mCherry groups). Schematics (d) and (e) made with Biorender.com.
Extended Data Fig. 2 Acutely isolated Gq-NGOxtr neurons depolarize during CNO bath application.
(a) Gq-NGOxtr neurons expressing mCherry acutely dissociated from the mouse NG are visualized with DIC and epifluorescence microscopy. (b, non-glowing, top) Representative whole-cell current clamp recordings of control NG neurons or (red glowing, bottom) neurons expressing Gq-mCherry. After a 60-s baseline recording, CNO (10 µM) was bath applied for 5 min. (c, left) Average membrane potentials of neurons at baseline and CNO were significantly different between groups (2-Way ANOVA). Multiple comparisons demonstrate that control neurons exposed to CNO failed to depolarize (Tukey post hoc) while CNO significantly depolarized Gq-DGOxtr neurons (Tukey post hoc). (c, right) The same data as (c, left) expressed as the Δ membrane potential during CNO application. CNO significantly depolarized membrane potential in Gq-NGOxtr compared to control neurons (unpaired, two-tailed t-test). Center line is median, edges show quartiles, and error bars are min/max. Recordings acquired from a total of 6 Gq and 5 Control neurons; n = 2 mice.
Extended Data Fig. 3 Representative graphs of individual temperature traces following CNO administration.
CNO (0.3 mg/kg i.p.) was administered at ZT11. Data expressed in 10 min bins.
Extended Data Fig. 4 Acute chemogenetic activation of NGOxtr results in decreased (a) food intake and (b) core body temperature in female mice.
CNO (0.3 mg/kg i.p.) was administered at ZT11. n = 9 mice. Data represented as mean ± SEM. Within subjects 2-way repeated measures ANOVA, Šídák’s multiple comparisons test, *p < 0.05.
Extended Data Fig. 5 The effects of acute CNO administration are recapitulated in male Gq-NGOxtr mice maintained on high fat diet.
Impact of CNO (0.3 mg/kg i.p.) or saline administered at ZT11 on hourly (a) food and (b) water intake, (c) oxygen consumption (VO2), (d) respiratory exchange ratio (RER), (e) body temperature, (f) systolic blood pressure (SBP), (g) heart rate (HR) and (h) change in body weight in Gq-NGOxtr mice (n = 7). Data represented as mean ± SEM. (a-g) Within subjects two-way repeated measures ANOVA with Šídák’s multiple comparisons test, (h) Paired, two-tailed t-test, *p < 0.05.
Extended Data Fig. 6 Acute activation of NGOxtr promotes vigilance and reduces locomotor activity.
Schematics of the (a) light dark box (LDB), (d) elevated plus maze (EPM) and (g) open field (OF) arena. Gq-NGOxtr made (b) fewer entries into the light and (c) spent less time in the light side of the LDB. Gq-NGOxtr mice (e) made fewer entries and (f) travelled less distance in the EPM. Gq-NGOxtr (h) made fewer center entries and (i) travelled less in the OF. (b,c,e,f) n = 10 CON-NGOxtr, 12 Gq-NGOxtr; (h) n = 14 CON-NGOxtr, 13 Gq-NGOxtr; (i) n = 14 CON-NGOxtr, 12 Gq-NGOxtr. Unpaired, two-tailed t-tests. Schematics (a, d, g) made with Biorender.com.
Extended Data Fig. 7 Cardiometabolic effects of chronic CNO administration in CON-NGOxtr mice.
CNO (0.3 mg/kg, i.p.) was administered (left) every other day for 11 days at ZT11 (1 h before lights off) or (right) ZT23 (1 h before lights on). Impact of chronic CNO administration on (a,c) food intake, (b, d) water intake, (e, g) body temperature, (f, h) VO2, (i, k) RER, (j, l) SBP or (m, n) HR. CON-NGOxtr data are averaged between baseline (2 days), no injection (5 days) and CNO injection days (6 days). (a,b,f,i) n = 15; (c, d, e, g, h, m, n) n = 7; (j,l) n = 6. Within-subject two-way repeated measures ANOVA with Tukey’s multiple comparisons test. *p < 0.05 BASELINE vs CNO INJ, #p < 0.05 NO INJ vs CNO INJ, &p < 0.05 BASELINE vs NO INJ.
Extended Data Fig. 8 Chronic administration of CNO (0.3 mg/kg i.p.) to male Gq-NGOxtr mice results in (a) weightloss attributed to (b) loss in fat mass but not (c) lean mass.
n = 8 mice. Within subject two-way repeated measures ANOVA and Šídák’s multiple comparisons test.
Extended Data Fig. 9 Chronic activation of NGOxtr does not induce anxiety-like behavior or reduce social preference.
Schematics of the (a) light dark box (LDB), (d) elevated plus maze (EPM) and (g) three-chamber social interaction tests. (b) Entries into and (c) duration of time spent in the light side of the LDB did not differ between groups. (e) Open arm entries and (f) distance travelled in the EPM did not differ between groups. Chronic NGOxtr activation did not affect (h) preference for investigating a novel mouse or (i) distance travelled in the three-chamber social interaction test. n = 8 CON-NGOxtr, 7 Gq-NGOxtr. Unpaired, two-tailed t-tests. Schematics (a, d, g) made with Biorender.com.
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Scott, K.A., Tan, Y., Johnson, D.N. et al. Mechanosensation of the heart and gut elicits hypometabolism and vigilance in mice. Nat Metab 7, 263–275 (2025). https://doi.org/10.1038/s42255-024-01205-6
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DOI: https://doi.org/10.1038/s42255-024-01205-6
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