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AgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids

Abstract

Phospholipid levels are influenced by peripheral metabolism. Within the central nervous system, synaptic phospholipids regulate glutamatergic transmission and cortical excitability. Whether changes in peripheral metabolism affect brain lipid levels and cortical excitability remains unknown. Here, we show that levels of lysophosphatidic acid (LPA) species in the blood and cerebrospinal fluid are elevated after overnight fasting and lead to higher cortical excitability. LPA-related cortical excitability increases fasting-induced hyperphagia, and is decreased following inhibition of LPA synthesis. Mice expressing a human mutation (Prg-1R346T) leading to higher synaptic lipid-mediated cortical excitability display increased fasting-induced hyperphagia. Accordingly, human subjects with this mutation have higher body mass index and prevalence of type 2 diabetes. We further show that the effects of LPA following fasting are under the control of hypothalamic agouti-related peptide (AgRP) neurons. Depletion of AgRP-expressing cells in adult mice decreases fasting-induced elevation of circulating LPAs, as well as cortical excitability, while blunting hyperphagia. These findings reveal a direct influence of circulating LPAs under the control of hypothalamic AgRP neurons on cortical excitability, unmasking an alternative non-neuronal route by which the hypothalamus can exert a robust impact on the cortex and thereby affect food intake.

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Fig. 1: Fasting increases synaptic active LPA subtypes in the brain and enhances glutamatergic transmission.
Fig. 2: Fasting-induced hyperphagia is regulated by cortical synaptic lipid signalling.
Fig. 3: Synaptic lipid signalling modulates body weight under both control and high-fat diets.
Fig. 4: Fasting-induced hyperphagia depends on AgRP circuit integrity.

Data availability

The data that support the findings of our study can be found in the Source Data provided with this article. Expression data of Enpp2/Atx and Prg-1/Lppr4 were analysed using the Allen Mouse Brain Atlas.

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Acknowledgments

We thank C. Ernest for proofreading the manuscript. This work was supported by Deutsche Forschungsgemeinschaft (nos. FB 1039, 1080, 1193 and 1451) to J.V., R.N., I.T., F.Z. and S.G.; by Germany´s Excellence Strategy (no. EXC 2030, 390661388) to J.V.; by the European Research Council (nos. ERC-AG ‘LiPsyD’ and ERC-PoC ‘PsychAid’) to R.N.; by the Boehringer-Ingelheim Foundation to J.V. and S.G.; by Stiftung Rheinland-Pfalz to J.V., R.N. and F.Z.; by InfectControl (nos. 03ZZ0826 and 03ZZ0835 to Y.L. and F.K., respectively); by the German Research Foundation (FOR2107, nos. DA1151/5-1 and DA1151/5-2 to U.D.; SFB-TRR58, nos. C09 and Z02 to U.D.); and by the Interdisciplinary Center for Clinical Research of the Medical Faculty of Münster (no. Dan3/012/17 to U.D.). SHIP is part of the Community Medicine Research net of the University of Greifswald, which receives grants from the Federal Ministry of Education and Research (nos. 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide SNP typing in SHIP has been supported by a joint grant from Siemens Healthineers, Erlangen and the Federal Ministry of Education and Research (no. 03ZIK012); by the European Union and European Social Fund grant (no. EFOP-3.6.2-16-2017-0008); by an NKFIH grant (no. KKP126998) to B.R.; and by NIH grant nos. AG052005, AG067329 and DK126447 and a Klarman Family Foundation Grant to T.L.H.

Author information

Authors and Affiliations

Authors

Contributions

J.V., R.N. and T.L.H. designed and supervised experiments and wrote the paper. Electrophysiological and behavioural experiments were performed by H.E., B.S., Z.-W.L., M.S.-P., B.R., J.B., W.F., N.S., G.H. and K.R. I.T., Y.S., I.F.S., R.G., F.K. and Y.L. performed mass spectrometry analyses and analysed data. M.M. was involved in data analysis and statistical analysis. R.N. and F.Z. founded the Gutenberg Brain Study, which provided human data. U.D. provided human data from both the Münster Neuroimaging Cohort and the FOR2107 consortium. H.J.G. provided human data from the Study of Health in Pomerania (Ship-O and Ship-Trend). I.T., N.O., S.G., F.Z. and U.D. provided important critical input to the manuscript.

Corresponding authors

Correspondence to Tamas L. Horvath, Robert Nitsch or Johannes Vogt.

Ethics declarations

Competing interests

H.J.G. has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag, as well as research funding from Fresenius Medical Care. The other authors declare no competing interests.

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Nature Metabolism thanks Vytas Bankaitis, Scott E. Kanoski and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ashley Castellanos-Jankiewicz, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 ATX and PRG-1 expression in cortical neurons.

a. Atx expression as shown by in-situ hybridization is present in the cortex and in the choroid ventricular plexus. Interestingly, strong expression in the cortex can be observed in the upper cortical layers (most prominent in layer II), which are important for cortical information processing. Image is adapted from the Allen Institute for Brain Science (2004). Allen Mouse Brain Atlas [532631] (mouse.brain-map.org). b-f. PRG-1 expression, as demonstrated by the ß-Gal reporter (for genetic details see Trimbuch et al., 2009), is predominantly found in the layers 2/3, 4 and 6 of the neocortex (visual cortex [A], auditory cortex [B], primary motor cortex [M1, C], dorsomedial prefrontal cortex [dmPFC,C] and primary sensory cortex [S1BF, F]). Strong expression was also found in the hippocampal formation (shown in E), as previously demonstrated. g-i. Staining for inhibitory neurons (GAD67, parvalbumin [PV] and calretinin [CR]) in the primary somatosensory cortex revealed no expression of PRG-1 in interneurons. Note the strong perisomatic inhibitory synapses of the excitatory, PRG-1-expressing neurons (arrowheads in the inserts in G and H). j. PRG-1 expression was detected in pyramidal (excitatory) neurons of the layer II, which express calbindin. Note the clear apical dendrites of these pyramidal neurons (arrowheads). PRG-1 expression as displayed in Fig. 1b-j was validated in at least 3 independent experiments. Scale bars: b-e 250 µm, f-j 100 µm, insets 15 µm.

Extended Data Fig. 2 LPA 18:1 is a synaptic active LPA.

a. Original traces of patched neurons before and after LPA 18:1 application suggest higher number of miniature inward currents (mEPSCs) when compared to values before LPA 18:1 application b. Quantitative analysis of mEPSC frequencies following LPA 18:1 application were significantly increased when compared to baseline values before LPA 18:1 application (n = 10; P = 0.0327, repeated measures one-way ANOVA). Data was calculated in % of the mean baseline over 3 min before drug application. c. For better evaluation, mean of the baseline of individual neurons over 3 min before LPA 18:1 stimulation was compared to that during the first 3 min after LPA 18:1 application finding significant differences (n = 10, P = 0.027, two-tailed Wilcoxon matched-pairs signed rank test). d. Original traces before and following of LPA 18:0 application show comparable mEPSCs. e,f. Quantitative analysis revealed no significant effect of LPA 18:0 application on mEPSC frequency (n = 9; repeated measures one-way ANOVA). Before and after LPA 18:0 application mean values of individual neurons were calculated as described above and shown in f (n = 8, two-tailed Wilcoxon matched-pairs signed rank test). Points and bars in b and e represent mean and s.e.m.

Source data

Extended Data Fig. 3 Fasting increases cortex-related exploratory behavior.

a. Experimental design. b. Fasting increased exploration (P < 0.0001), which was reduced to control values by ATX inhibition (P < 0.0001; n = 13 control mice [C], n = 14 fasted mice [F], and n = 12 PF8380-treated fasted mice [F + PF8380]; one-way ANOVA with Bonferroni correction). c. Cortical ATX-deletion (AtxΔcortex) did not affect exploration (n = 20 WT and 16 AtxΔcortex mice, two-tailed Mann-Whitney test) while it significantly reduced exploratory behavior after fasting (n = 21 fasted WT [F WT] and 19 fasted AtxΔcortex [F AtxΔcortex] mice; P = 0.0155, two-tailed t-test). d. Cortical ATX-deletion reduced fasting-induced exploration to non-fasting conditions (n = 16 non-fasted mice AtxΔcortex [C AtxΔcortex] mice and 16 fasted AtxΔcortex [F AtxΔcortex] mice, two-tailed t-test). e. ATX inhibition did not alter exploratory behavior of fasted AtxΔcortex mice (n = 6 fasted AtxΔcortex mice [F AtxΔcortex] and 8 fasted AtxΔcortex + PF8380 mice [F AtxΔcortex + PF8380], two-tailed t-test). f. Exploratory behavior of Lpa2-/- mice under baseline conditions and after fasting (n = 16 WT and n = 27 Lpa2-/- mice, two-tailed Mann-Whitney test; n = 11 fasted WT and 16 fasted Lpa2-/- [F Lpa2-/-] mice, P = 0.032, two-tailed t-test). g. ATX inhibition by PF8380 did not alter fasting-induced exploratory behavior in Lpa2-/- mice when compared to non-treated, fasted Lpa2-/- mice (n = 9 fasted Lpa2-/- mice [F Lpa2-/-] and 10 fasted Lpa2-/- +PF8380 [F Lpa2-/- +PF8380] mice, two-tailed Mann-Whitney test). h. Prg-1R346T/+ mice did show normal exploratory behavior under non-fasting conditions (n = 8 WT and n = 11 Prg-1R346T/+ mice, one-tailed t-test) while fasting significantly increased exploration (n = 20 fasted WT [F WT] and 23 fasted Prg-1R346T/+ mice [F Prg-1R346T/+]; P = 0.034, one-tailed t-test). Dots represent single values, bars represent mean and s.e.m., *p < 0.05, ****p < 0.0001. Illustration was created with BioRender.

Source data

Extended Data Fig. 4 Overnight fasting does not alter basic locomotion.

a. Experimental design. b. PF8380 i.p. application (30 mg/kg body weight) significantly reduced LPA subtype levels in the CSF. Note that some values in the CSF after ATX inhibition by PF8380 were below the lower level of quantification and set to 0 (n = 4 WT and 6 WT + PF8380 for LPA 16:0, n = 6 WT and WT + PF8380 for LPA 18:1, n = 5 WT and 6 WT + PF8380 for LPA 18:2 and LPA 20:4, group differences for LPA 16:0 97.6%, for LPA 18:1 99.2%, for LPA 18:2 84.5%, for LPA 20:4 69.9%,Bayesian analysis. Box plots and whiskers show data from min to max, line shows median; group differences * >80% or **>90%. c. Basic spontaneous motor function was not altered after fasting or after PF8380 treatment (n = 13 non-fasted WT [C], 15 fasted WT [F] and n = 15 fasted WT + PF8380 mice [F + PF8380], one-way ANOVA). d. Basic spontaneous motor function was not altered in AtxΔcortex mice under control conditions or after fasting [F] (n = 13 WT and fasted WT [F WT] mice and n = 12 AtxΔcortex mice [AtxΔcortex and F AtxΔcortex], two-tailed t-test). e. Basic spontaneous motor function was not altered in Lpa2-/- mice under control conditions or after fasting (n = 16 WT mice [WT and F WT] and n = 8 Lpa2-/- mice [Lpa2-/–and F Lpa2-/-], t-test). f. Basic spontaneous locomotion was not altered in Prg-1R346T/+ animals under control conditions or after fasting (n = 8 WT mice [WT and F WT] and n = 11 Prg-1R346T/+ mice [Prg-1R346T/+ and F Prg-1R346T/+], two-tailed Mann-Whitney test). Experimental design figures were created with BioRender.com. Dots show single values, bars show mean and s.e.m. Illustration was created with BioRender.

Source data

Extended Data Fig. 5 Altered synaptic lipid signaling is associated with increased body weight in mice and humans.

a. Fasting-induced hyperphagia was comparable in Prg-1+/- and Prg-1R346T/+ animals (n = 14 F Prg-1+/- and n = 13 F Prg-1R346T/+, two-sided t-test) b. Food consumption per hour of Prg-1R346T/+ and WT animals averaged over 24 hours (n = 20 WT and n = 23 Prg-1R346T/+, group differences 86,7%, Bayesian analysis). c. BMI was significantly increased in human PRG-1R345T/+ carriers (n = 58 PRG-1R346T/+ and n = 60 control subjects matched for sex, age, height and education, P = 0.0041, two-tailed Mann-Whitney test). d. Diabetes type 2 (DMT2) prevalence was significantly increased in male PRG-1R346T/+ carriers, which displayed a significantly higher odds ratio (OR) for DMT2 of 2.45 (p = 0.037, logistic regression adjusted for age, sex and cohort; n = 3947 control subjects with 443 individuals with diabetes; n = 32 PRG-1R345T/+ carriers with 7 individuals with diabetes; P = 0.0291, chi square test, p*<0.05). Graph shows number of diabetic individuals as a percentage of the corresponding group. i,j. PF8380 was quickly metabolized by human liver microsomes to a metabolite with 288 g∙mol-1 (n = 3; CLint > 100 µl ∙ (min ∙ mg)-1. Diclofenac was used as a positive control. Dots show single values, bars represent mean and SEM.*p < 0.05, ***p < 0.001, ****p < 0.0001, *group differences >80% for Bayesian analysis.

Source data

Extended Data Fig. 6 LPC and LPA levels in blood plasma and LPA concentrations in the CSF of fasted AgRPDTR and WT.

a. Blood plasma concentrations of total LPCs and 18:0 LPC in fasted AgRPDTR animals (n = 5 fasted WT and n = 8 fasted AgRPDTR mice, group differences 88.1% for total LPC and 86,8% for LPC 18:1, Bayesian analysis). b. Blood plasma levels of different LPA subtypes in fasted WT and fasted AgRPDTR animals (n = 6 for LPA 16:0, 18:0 and n = 7 for 18:2, 18:3 and 20:4 for fasted WT; n = 8 for LPA 18:0 and 7 for all other LPA subtypes for fasted AgRPDTR animals, group differences 79.7% for LPA 16:0, 84.4% for LPA 18:0, 68.4% for LPA 18:2, 85.7% for LPA 18:3, 55.1% for LPA 20:4, Bayesian analysis). c. CSF levels of different LPA subtypes in fasted WT and fasted AgRPDTR mice (n = 6 for LPA 18:2 and 7 for all other LPAs in fasted WT and n = 5 for fasted AgRPDTR mice, group differences 68.8% for LPA 16:0, 69.4% for LPA 18:0, 97.3% for LPA 18:2, 95.5% for LPA 20:4, Bayesian analysis). d. Individual CSF LPA levels displayed for corresponding animals show high variance (n = 6 for LPA 18:2 and 7 for all other LPAs in fasted WT and n = 5 for fasted AgRPDTR mice). e. Ratio calculated for different LPA subtypes to total LPA levels (n = 6 for LPA 18:2 and 7 for all other LPAs in fasted WT and n = 5 for fasted AgRPDTR mice, group differences for LPA 16:0 90.2%, for LPA 18:0 97.5%, for LPA 18:1 93.5%, for LPA 18:2 98.8%, for LPA 20:4 70.5%, Bayesian analysis). Whiskers represent min to max, box extends from the 25th to the 75th percentile, middle line represents the median. Points represent individual values. Group differences of * >80% or **>90% are shown for Bayesian analysis.

Source data

Extended Data Fig. 7 Expression of synaptic lipid modulating molecules ATX and PRG-1 in the prefrontal cortex.

a. Nissl stained coronal section of the prefrontal cortex reaching up to the medial prefrontal cortex (mPFC, ACA anterior cingular area) and corresponding to the coronal levels of the in-situ hybridizations shown for ATX and PRG-1. Scale bar: 800 µm b. ATX expression is predominantly found in the upper prefrontal cortex layers (especially in layers II/III). Data was validated in three experiments. c. PRG-1 is strongly expressed in the layers II/III of the prefrontal cortex but is also found at high expression levels in the layer IV. Data was validated in two experiments. Images are adapted from the Allen Institute for Brain Science (2004). Allen Mouse Brain Atlas [70613967 for Atx and 73992941 for Prg-1] (mouse.brain-map.org).

Extended Data Table 1 Group differences calculated as differences of the means are displayed as differences between the groups, which describes the ability to separate the compared groups. Accuracy ranges for the differences of the means ≥80% as well as an effect size ≥80% were considered significant, differences of the means ≥ 90% as well as an effect size ≥ 90% were considered highly significant (Johnson 2013)

Supplementary information

Supplementary Information

Supplementary methods for the Extended Data files and detailed description of Bayesian statistical methods, and references.

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Endle, H., Horta, G., Stutz, B. et al. AgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids. Nat Metab 4, 683–692 (2022). https://doi.org/10.1038/s42255-022-00589-7

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