Circulating Triglycerides Gate Dopamine-Associated Behaviors through DRD2-Expressing Neurons
Cell Metabolism. 2020-03-01; :
DOI: 10.1016/j.cmet.2020.02.010
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Berland C(1), Montalban E(2), Perrin E(3), Di Miceli M(4), Nakamura Y(5), Martinat M(4), Sullivan M(5), Davis XS(5), Shenasa MA(6), Martin C(2), Tolu S(7), Marti F(7), Caille S(8), Castel J(2), Perez S(3), Salinas CG(9), Morel C(2),
Hecksher-Sørensen J(10), Cador M(8), Fioramonti X(4), Tschöp MH(11), Layé S(4), Venance L(3), Faure P(7), Hnasko TS(12), Small DM(5), Gangarossa G(13), Luquet SH(14).
Author information:
(1)Université de Paris, BFA, UMR 8251, CNRS, F-75014 Paris, France; Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Neuherberg, Germany.
(2)Université de Paris, BFA, UMR 8251, CNRS, F-75014 Paris, France.
(3)Center for Interdisciplinary Research in Biology, College de France, INSERM U1050, CNRS UMR 7241, Labex Memolife, 75005 Paris, France.
(4)Université Bordeaux, INRA, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux, France.
(5)The Modern Diet and Physiology Research Center, New Haven, CT, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
(6)Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
(7)Sorbonne Université, CNRS UMR 8246, INSERM, Neurosciences Paris Seine, Institut de Biologie Paris-Seine, Paris, France.
(8)Université Bordeaux, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, CNRS, UMR5287, 33076 Bordeaux, France.
(9)Gubra ApS, Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark.
(10)Global Research, Novo Nordisk A/S, Måløv, Denmark; Gubra ApS, Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark.
(11)Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Neuherberg, Germany; Division of Metabolic Diseases, TUM, Munich, Germany; Institute for Advanced Study, TUM, Munich, Germany.
(12)Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Research Service VA San Diego Healthcare System, San Diego, CA 92161, USA.
(13)Université de Paris, BFA, UMR 8251, CNRS, F-75014 Paris, France.
(14)Université de Paris, BFA, UMR 8251, CNRS, F-75014 Paris, France; The Modern Diet and Physiology Research Center, New Haven, CT, USA.
Energy-dense food alters dopaminergic (DA) transmission in the mesocorticolimbic
(MCL) system and can promote reward dysfunctions, compulsive feeding, and weight
gain. Yet the mechanisms by which nutrients influence the MCL circuitry remain
elusive. Here, we show that nutritional triglycerides (TGs), a conserved
post-prandial metabolic signature among mammals, can be metabolized within the
MCL system and modulate DA-associated behaviors by gating the activity of
dopamine receptor subtype 2 (DRD2)-expressing neurons through a mechanism that
involves the action of the lipoprotein lipase (LPL). Further, we show that in
humans, post-prandial TG excursions modulate brain responses to food cues in
individuals carrying a genetic risk for reduced DRD2 signaling. Collectively,
these findings unveil a novel mechanism by which dietary TGs directly alter
signaling in the reward circuit to regulate behavior, thereby providing a new
mechanistic basis by which energy-rich diets may lead to (mal)adaptations in DA
signaling that underlie reward deficit and compulsive behavior.
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