Hypothalamic dopamine signalling regulates brown fat thermogenesis

Cintia Folgueira , Daniel Beiroa , Begoña Porteiro (1) , Manon Duquenne (2) , Emma Puighermanal (3) , Marcos Fondevila , Silvia Barja-Fernández , Rosalía Gallego (1) , René Hernández-Bautista , Cecilia Castelao , Ana Senra , Patricia Seoane-Collazo , Noemi Gómez-Lado , Pablo Aguiar , Diana Guallar , Miguel Fidalgo , Amparo Romero-Pico , Roger Adan , Clemence Blouet , Jose Luís Labandeira-García , Françoise Jeanrenaud , Imre Kalló (4) , Zsolt Liposits (5) , Javier Salvador , Vincent Prevot (2) , Carlos Dieguez (1) , Miguel Lopez (1) , Emmanuel Valjent (3) , Gema Frühbeck (6) , Luisa Seoane , Ruben Nogueiras (1)

1 USC - Universidade de Santiago de Compostela [Spain]
2 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
3 IGF - Institut de Génomique Fonctionnelle
4 Reproductive Neurobiology, Division of Women's Health, School of Medicine
5 Laboratory of Endocrine Neurobiology
6 Ciber Fisiopatologia Obesidad y Nutricion (CIBEROBN)

Dopamine signaling is a crucial part of the brain reward system and can affect feeding behavior. 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 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 CNS to regulate energy balance.

Domaines: Sciences du Vivant [q-bio]; Neurosciences [q-bio.NC]

Cintia Folgueira, Daniel Beiroa, Begoña Porteiro, Manon Duquenne, Emma Puighermanal, et al.. Hypothalamic dopamine signalling regulates brown fat thermogenesis. Nature Metabolism, 2019, 1 (8), pp.811-829. ⟨10.1038/s42255-019-0099-7⟩. ⟨hal-02400248⟩