Dopamine in the nucleus accumbens shell controls systemic glucose metabolism via the lateral hypothalamus and hepatic vagal innervation in rodents

Charlene Diepenbroek; Merel Rijnsburger; Astrid A S van Irsen; Leslie Eggels; Alexandre Kisner; Ewout Foppen; Unga A Unmehopa; Chloé Berland; Sophie Dólleman; Marene Hardonk; Céline Cruciani-Guglielmacci; Rudi Faust; Rick Wenning; Clarissa M Maya-Monteiro; Andries Kalsbeek; Yeka Aponte; Serge Luquet; Mireille J Serlie; Susanne E la Fleur

doi:10.1016/j.metabol.2023.155696

Dopamine in the nucleus accumbens shell controls systemic glucose metabolism via the lateral hypothalamus and hepatic vagal innervation in rodents

Charlene Diepenbroek, Merel Rijnsburger, Astrid A S van Irsen, Leslie Eggels, Alexandre Kisner, Ewout Foppen, Unga A Unmehopa, Chloé Berland, Sophie Dólleman, Marene Hardonk, Céline Cruciani-Guglielmacci, Rudi Faust, Rick Wenning, Clarissa M Maya-Monteiro, Andries Kalsbeek, Yeka Aponte, Serge Luquet, Mireille J Serlie, Susanne E la Fleur

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Abstract

BACKGROUND: Growing evidence demonstrates the role of the striatal dopamine system in the regulation of glucose metabolism. Treatment with dopamine antagonists is associated with insulin resistance and hyperglycemia, while dopamine agonists are used in treatment of diabetes mellitus type 2. The mechanism underlying striatal dopamine effects in glucose metabolism, however is not fully understood. Here, we provide mechanistic insights into the role of nucleus accumbens shell (sNAc) dopaminergic signaling in systemic glucose metabolism.

METHODS: Endogenous glucose production (EGP), blood glucose and mRNA expression in the lateral hypothalamic area (LHA) in male Wistar rats were measured following infusion of vanoxerine (VNX, dopamine reuptake inhibitor) in the sNAc. Thereafter, we analyzed projections from sNAc Drd1-expressing neurons to LHA using D1-Cre male Long-Evans rats, Cre-dependent viral tracers and fluorescence immunohistochemistry. Brain slice electrophysiology in adult mice was used to study spontaneous excitatory postsynaptic currents of sNAc Drd1-expressing neurons following VNX application. Finally, we assessed whether GABAergic LHA activity and hepatic vagal innervation were required for the effect of sNAc-VNX on glucose metabolism by combining infusion of sNAc-VNX with LHA-bicuculline, performing vagal recordings and combining infusion of sNAc-VNX with hepatic vagal denervation.

RESULTS: VNX infusion in the sNAc strongly decreased endogenous glucose production, prevented glucose increases over time, reduced Slc17A6 and Hcrt mRNA in LHA, and increased vagal activity. Furthermore, sNAc Drd1-expressing neurons increased spontaneous firing following VNX application, and viral tracing of sNAc Drd1-expressing neurons revealed direct projections to LHA with on average 67 % of orexin cells directly targeted by sNAc Drd1-expressing neurons. Importantly, the sNAc-VNX-induced effect on glucose metabolism was dependent on GABAergic signaling in the LHA and on intact hepatic vagal innervation.

CONCLUSIONS: We show that sNAc dopaminergic signaling modulates hepatic glucose metabolism through GABAergic inputs to glutamatergic LHA cells and hepatic vagal innervation. This demonstrates that striatal control of glucose metabolism involves a dopaminergic sNAc-LHA-liver axis and provides a potential explanation for the effects of dopamine agonists and antagonists on glucose metabolism.

Original language	English
Pages (from-to)	155696
Journal	Metabolism: Clinical and Experimental
Volume	150
DOIs	https://doi.org/10.1016/j.metabol.2023.155696
Publication status	Published - 02 Jan 2024

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10.1016/j.metabol.2023.155696

Diepenbroek2023Final published version, 5.87 MBLicence: CC BY

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Diepenbroek, C., Rijnsburger, M., van Irsen, A. A. S., Eggels, L., Kisner, A., Foppen, E., Unmehopa, U. A., Berland, C., Dólleman, S., Hardonk, M., Cruciani-Guglielmacci, C., Faust, R., Wenning, R., Maya-Monteiro, C. M., Kalsbeek, A., Aponte, Y., Luquet, S., Serlie, M. J., & la Fleur, S. E. (2024). Dopamine in the nucleus accumbens shell controls systemic glucose metabolism via the lateral hypothalamus and hepatic vagal innervation in rodents. Metabolism: Clinical and Experimental, 150, 155696. https://doi.org/10.1016/j.metabol.2023.155696

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title = "Dopamine in the nucleus accumbens shell controls systemic glucose metabolism via the lateral hypothalamus and hepatic vagal innervation in rodents",

abstract = "BACKGROUND: Growing evidence demonstrates the role of the striatal dopamine system in the regulation of glucose metabolism. Treatment with dopamine antagonists is associated with insulin resistance and hyperglycemia, while dopamine agonists are used in treatment of diabetes mellitus type 2. The mechanism underlying striatal dopamine effects in glucose metabolism, however is not fully understood. Here, we provide mechanistic insights into the role of nucleus accumbens shell (sNAc) dopaminergic signaling in systemic glucose metabolism.METHODS: Endogenous glucose production (EGP), blood glucose and mRNA expression in the lateral hypothalamic area (LHA) in male Wistar rats were measured following infusion of vanoxerine (VNX, dopamine reuptake inhibitor) in the sNAc. Thereafter, we analyzed projections from sNAc Drd1-expressing neurons to LHA using D1-Cre male Long-Evans rats, Cre-dependent viral tracers and fluorescence immunohistochemistry. Brain slice electrophysiology in adult mice was used to study spontaneous excitatory postsynaptic currents of sNAc Drd1-expressing neurons following VNX application. Finally, we assessed whether GABAergic LHA activity and hepatic vagal innervation were required for the effect of sNAc-VNX on glucose metabolism by combining infusion of sNAc-VNX with LHA-bicuculline, performing vagal recordings and combining infusion of sNAc-VNX with hepatic vagal denervation.RESULTS: VNX infusion in the sNAc strongly decreased endogenous glucose production, prevented glucose increases over time, reduced Slc17A6 and Hcrt mRNA in LHA, and increased vagal activity. Furthermore, sNAc Drd1-expressing neurons increased spontaneous firing following VNX application, and viral tracing of sNAc Drd1-expressing neurons revealed direct projections to LHA with on average 67 % of orexin cells directly targeted by sNAc Drd1-expressing neurons. Importantly, the sNAc-VNX-induced effect on glucose metabolism was dependent on GABAergic signaling in the LHA and on intact hepatic vagal innervation.CONCLUSIONS: We show that sNAc dopaminergic signaling modulates hepatic glucose metabolism through GABAergic inputs to glutamatergic LHA cells and hepatic vagal innervation. This demonstrates that striatal control of glucose metabolism involves a dopaminergic sNAc-LHA-liver axis and provides a potential explanation for the effects of dopamine agonists and antagonists on glucose metabolism.",

author = "Charlene Diepenbroek and Merel Rijnsburger and {van Irsen}, {Astrid A S} and Leslie Eggels and Alexandre Kisner and Ewout Foppen and Unmehopa, {Unga A} and Chlo{\'e} Berland and Sophie D{\'o}lleman and Marene Hardonk and C{\'e}line Cruciani-Guglielmacci and Rudi Faust and Rick Wenning and Maya-Monteiro, {Clarissa M} and Andries Kalsbeek and Yeka Aponte and Serge Luquet and Serlie, {Mireille J} and {la Fleur}, {Susanne E}",

note = "Copyright {\textcopyright} 2023. Published by Elsevier Inc.",

year = "2024",

month = jan,

day = "2",

doi = "10.1016/j.metabol.2023.155696",

language = "English",

volume = "150",

pages = "155696",

journal = "Metabolism: Clinical and Experimental",

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Diepenbroek, C, Rijnsburger, M, van Irsen, AAS, Eggels, L, Kisner, A, Foppen, E, Unmehopa, UA, Berland, C, Dólleman, S, Hardonk, M, Cruciani-Guglielmacci, C, Faust, R, Wenning, R, Maya-Monteiro, CM , Kalsbeek, A, Aponte, Y, Luquet, S, Serlie, MJ & la Fleur, SE 2024, 'Dopamine in the nucleus accumbens shell controls systemic glucose metabolism via the lateral hypothalamus and hepatic vagal innervation in rodents', Metabolism: Clinical and Experimental, vol. 150, pp. 155696. https://doi.org/10.1016/j.metabol.2023.155696

Dopamine in the nucleus accumbens shell controls systemic glucose metabolism via the lateral hypothalamus and hepatic vagal innervation in rodents. / Diepenbroek, Charlene; Rijnsburger, Merel; van Irsen, Astrid A S et al.
In: Metabolism: Clinical and Experimental, Vol. 150, 02.01.2024, p. 155696.

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

TY - JOUR

T1 - Dopamine in the nucleus accumbens shell controls systemic glucose metabolism via the lateral hypothalamus and hepatic vagal innervation in rodents

AU - Diepenbroek, Charlene

AU - Rijnsburger, Merel

AU - van Irsen, Astrid A S

AU - Eggels, Leslie

AU - Kisner, Alexandre

AU - Foppen, Ewout

AU - Unmehopa, Unga A

AU - Berland, Chloé

AU - Dólleman, Sophie

AU - Hardonk, Marene

AU - Cruciani-Guglielmacci, Céline

AU - Faust, Rudi

AU - Wenning, Rick

AU - Maya-Monteiro, Clarissa M

AU - Kalsbeek, Andries

AU - Aponte, Yeka

AU - Luquet, Serge

AU - Serlie, Mireille J

AU - la Fleur, Susanne E

PY - 2024/1/2

Y1 - 2024/1/2

N2 - BACKGROUND: Growing evidence demonstrates the role of the striatal dopamine system in the regulation of glucose metabolism. Treatment with dopamine antagonists is associated with insulin resistance and hyperglycemia, while dopamine agonists are used in treatment of diabetes mellitus type 2. The mechanism underlying striatal dopamine effects in glucose metabolism, however is not fully understood. Here, we provide mechanistic insights into the role of nucleus accumbens shell (sNAc) dopaminergic signaling in systemic glucose metabolism.METHODS: Endogenous glucose production (EGP), blood glucose and mRNA expression in the lateral hypothalamic area (LHA) in male Wistar rats were measured following infusion of vanoxerine (VNX, dopamine reuptake inhibitor) in the sNAc. Thereafter, we analyzed projections from sNAc Drd1-expressing neurons to LHA using D1-Cre male Long-Evans rats, Cre-dependent viral tracers and fluorescence immunohistochemistry. Brain slice electrophysiology in adult mice was used to study spontaneous excitatory postsynaptic currents of sNAc Drd1-expressing neurons following VNX application. Finally, we assessed whether GABAergic LHA activity and hepatic vagal innervation were required for the effect of sNAc-VNX on glucose metabolism by combining infusion of sNAc-VNX with LHA-bicuculline, performing vagal recordings and combining infusion of sNAc-VNX with hepatic vagal denervation.RESULTS: VNX infusion in the sNAc strongly decreased endogenous glucose production, prevented glucose increases over time, reduced Slc17A6 and Hcrt mRNA in LHA, and increased vagal activity. Furthermore, sNAc Drd1-expressing neurons increased spontaneous firing following VNX application, and viral tracing of sNAc Drd1-expressing neurons revealed direct projections to LHA with on average 67 % of orexin cells directly targeted by sNAc Drd1-expressing neurons. Importantly, the sNAc-VNX-induced effect on glucose metabolism was dependent on GABAergic signaling in the LHA and on intact hepatic vagal innervation.CONCLUSIONS: We show that sNAc dopaminergic signaling modulates hepatic glucose metabolism through GABAergic inputs to glutamatergic LHA cells and hepatic vagal innervation. This demonstrates that striatal control of glucose metabolism involves a dopaminergic sNAc-LHA-liver axis and provides a potential explanation for the effects of dopamine agonists and antagonists on glucose metabolism.

AB - BACKGROUND: Growing evidence demonstrates the role of the striatal dopamine system in the regulation of glucose metabolism. Treatment with dopamine antagonists is associated with insulin resistance and hyperglycemia, while dopamine agonists are used in treatment of diabetes mellitus type 2. The mechanism underlying striatal dopamine effects in glucose metabolism, however is not fully understood. Here, we provide mechanistic insights into the role of nucleus accumbens shell (sNAc) dopaminergic signaling in systemic glucose metabolism.METHODS: Endogenous glucose production (EGP), blood glucose and mRNA expression in the lateral hypothalamic area (LHA) in male Wistar rats were measured following infusion of vanoxerine (VNX, dopamine reuptake inhibitor) in the sNAc. Thereafter, we analyzed projections from sNAc Drd1-expressing neurons to LHA using D1-Cre male Long-Evans rats, Cre-dependent viral tracers and fluorescence immunohistochemistry. Brain slice electrophysiology in adult mice was used to study spontaneous excitatory postsynaptic currents of sNAc Drd1-expressing neurons following VNX application. Finally, we assessed whether GABAergic LHA activity and hepatic vagal innervation were required for the effect of sNAc-VNX on glucose metabolism by combining infusion of sNAc-VNX with LHA-bicuculline, performing vagal recordings and combining infusion of sNAc-VNX with hepatic vagal denervation.RESULTS: VNX infusion in the sNAc strongly decreased endogenous glucose production, prevented glucose increases over time, reduced Slc17A6 and Hcrt mRNA in LHA, and increased vagal activity. Furthermore, sNAc Drd1-expressing neurons increased spontaneous firing following VNX application, and viral tracing of sNAc Drd1-expressing neurons revealed direct projections to LHA with on average 67 % of orexin cells directly targeted by sNAc Drd1-expressing neurons. Importantly, the sNAc-VNX-induced effect on glucose metabolism was dependent on GABAergic signaling in the LHA and on intact hepatic vagal innervation.CONCLUSIONS: We show that sNAc dopaminergic signaling modulates hepatic glucose metabolism through GABAergic inputs to glutamatergic LHA cells and hepatic vagal innervation. This demonstrates that striatal control of glucose metabolism involves a dopaminergic sNAc-LHA-liver axis and provides a potential explanation for the effects of dopamine agonists and antagonists on glucose metabolism.

U2 - 10.1016/j.metabol.2023.155696

DO - 10.1016/j.metabol.2023.155696

M3 - Article

C2 - 37804881

SN - 0026-0495

VL - 150

SP - 155696

JO - Metabolism: Clinical and Experimental

JF - Metabolism: Clinical and Experimental

ER -

Dopamine in the nucleus accumbens shell controls systemic glucose metabolism via the lateral hypothalamus and hepatic vagal innervation in rodents

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