Hypothalamic dopamine signalling regulates brown fat thermogenesis

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Abstract

Dopamine signalling is a crucial part of the brain reward system and can affect feeding behaviour. Dopamine receptors are also expressed in the hypothalamus, which is known to control energy metabolism in peripheral tissues. Here we show that pharmacological or chemogenetic stimulation of dopamine receptor 2 (D2R) expressing cells in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in rodents in a feeding-independent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system and orexin system to exert its action and involves inhibition of PI3K in the LHA/ZI. We further demonstrate that, as early as 3 months after the onset of treatment, patients treated with the D2R agonist cabergoline experience an increase in energy expenditure that persists for one year, leading to total body weight and fat loss through a prolactin-independent mechanism. Our results may provide a mechanistic explanation for how clinically used D2R agonists act in the central nervous system to regulate energy balance.

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Fig. 1: Chronic central infusion of bromocriptine reduces diet-induced obesity.
Fig. 2: Stimulation of D2R in the LHA/ZI stimulates BAT activity.
Fig. 3: Knockdown of D2R in the LHA/ZI blunts bromocriptine-induced weight loss.
Fig. 4: D2R action in GABAergic neurons requires orexin to modulate BAT.
Fig. 5: PKA mediates the effects of bromocriptine on BAT.
Fig. 6: S6 mediates the effects of bromocriptine on BAT.
Fig. 7: Cabergoline decreases body weight and increases REE in patients.

Data availability

The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We would like to thank L. Casas for her excellent technical assistance. This work has been supported by grants from FEDER, Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación (C.D.: BFU2017-87721; M.L.: SAF2015-71026-R and BFU2015-70454-REDT/Adipoplast; R.N.: BFU2015-70664R), and Centro Singular de Investigación de Galicia accreditation 2016–2019, ED431G/05) and the European Regional Development Fund (ERDF), Xunta de Galicia (M.L.: 2015-CP079 and 2016-PG068; R.N.: 2015-CP080 and 2016-PG057), Fundación BBVA (R.N.), Fundación Atresmedia (M.L. and R.N.), Instituto de Salud Carlos III and cofunded by FEDER (L.M.S.:PI15/01272 and PI18/01890). The research leading to these results has also received funding from the European Community’s H2020 Framework Programme under the following grant: ERC Synergy Grant-2019-WATCH-810331 to V.P. and R.N. Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds. This work was supported by Inserm, Fondation pour la Recherche Médicale, ANR-EPITRACES (E.V.).

Author information

C.F., D.B., B.P., M.D., E.P., M.F.-F., S.B.-F., R.G., R.H.-B., C.C., A.S., P.S.-C., N.G.-L., P.A., D.G., M.F., A.R.-R., I.K. and Z.L. carried out the experiments. R.A., C.B., J.L.L.-B. and F.J. generated viral vectors and animal models. J.S. and G.F. performed the assays in patients. C.F., V.P., C.D., M.L., E.V., L.M.S. and R.N. designed and planned the study. All authors contributed to the preparation of the manuscript.

Correspondence to Luisa M. Seoane or Ruben Nogueiras.

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Supplementary Table 1

Antisense oligonucleotide for rat MCH and rat prepro-OX.

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