The Dopamine Receptor Subtype 2 (DRD2) Regulates the Central Reinforcing Actions of Dietary Lipids in Humans and Rodents

Emerging evidence suggests that energy-dense food alters dopaminergic (DA) transmission in the mesocorticolimbic (MCL) system and can promote the development of compulsive-like feeding, reward dysfunction, and ultimately weight gain. Yet the mechanisms by which metabolic signals influence MCL circuitry to control behavior remain poorly understood. Circulating triglycerides (TG) are a conserved post-prandial metabolic signature among mammals and high plasma TG are associated with reduced reward responsiveness in humans. Here, we show that the TG-processing enzyme lipoprotein lipase (LPL) is enriched throughout the MCL of both mouse and human, including DA-releasing neurons in the ventral tegmental area and DA-receptive neurons in the striatum. Using brain-specific TG delivery in mice, we show that nutritional TG are metabolized within the MCL system where they acutely control D2 DA receptor (DRD2) signaling. We also show that TG are directly reinforcing in mice, and that central TG sensing relies on LPL activity in the MCL. Likewise, in humans, post-prandial TG excursions modulate brain response to food cues in MCL with the direction of the association determined by a DRD2 dependent genotype. Collectively, these findings reveal a mechanism by which dietary TG directly alter MCL signaling to regulate behavior, providing a new mechanistic basis by which energy-rich diets can lead to adaptations in DA signaling that underlie compulsive behavior.