Striatal dopamine 2 receptor upregulation during development predisposes to diet-induced obesity by reducing energy output in mice
Proceedings of the National Academy of Sciences of the United States of America
Dopaminergic signaling in the striatum, particularly at dopamine 2 receptors (D2R), has been a topic of active investigation in obesity research in the past decades. However, it still remains unclear whether variations in striatal D2Rs modulate the risk for obesity and if so in which direction. Human studies have yielded contradictory findings that likely reflect a complex nonlinear relationship, possibly involving a combination of causal effects and compensatory changes. Animal work indicates
... mal work indicates that although chronic obesogenic diets reduce striatal D2R function, striatal D2R down-regulation does not lead to obesity. In this study, we evaluated the consequences of striatal D2R up-regulation on body-weight gain susceptibility and energy balance in mice. We used a mouse model of D2R overexpression (D2R-OE) in which D2Rs were selectively up-regulated in striatal medium spiny neurons. We uncover a pathological mechanism by which striatal D2R-OE leads to reduced brown adipose tissue thermogenesis, reduced energy expenditure, and accelerated obesity despite reduced eating. We also show that D2R-OE restricted to development is sufficient to promote obesity and to induce energybalance deficits. Together, our findings indicate that striatal D2R-OE during development persistently increases the propensity for obesity by reducing energy output in mice. This suggests that early alterations in the striatal dopamine system could represent a key predisposition factor toward obesity. development | dopamine D2 receptor | metabolism | obesity | striatum D opaminergic (DA) signaling in the striatum, particularly at dopamine 2 receptors (D2R), is one of the most widely studied neurotransmitter systems in obesity (for a review see refs. 1-3). However, despite two decades of research in the field, the contribution of D2Rs to human obesity remains unclear. Pioneer genetic linkage studies showed that the A1 allele of the Taq1A polymorphism, which is thought to associate with a 20-30% reduction in striatal D2R levels, is correlated with higher risk of obesity. Several other reports, however, did not confirm this linkage (reviewed in refs. 3 and 4) . PET studies, which provide a more direct picture of striatal D2R function, have also yielded inconsistent results. A landmark PET study initially reported lower striatal D2/D3R availability in obese subjects (5), a finding later replicated by others (6, 7) . Most of these studies, however, employed severely obese subjects [body mass index (BMI) >45] (see ref. 8). In contrast, more recent investigations found an absence of correlation (9-11) or a positive correlation (8, 9, (12) (13) (14) between striatal D2/D3R availability and BMI. Accordingly, one way to reconcile these findings would be that low D2R might be a consequence of chronic obesity, rather than a cause, while instead high D2R could act to increase the risk for obesity. The available animal literature corroborates these possibilities. Obesogenic diets generally lead to reduced striatal D2R function in rodents (15) (16) (17) (18) . Down-regulation of striatal D2Rs reduces locomotion but does not lead to obesity in mice (16). Thus, one key question is whether high levels of striatal D2R might be causally involved in obesity development. In the present study, D2Rs were selectively overexpressed (D2R-OE) in medium spiny neurons (MSNs) (19, 20) , the main output neurons of the striatum. We examined whether D2R-OE increased body weight (BW) (and related metabolic endpoints) at basal state or on a high-fat diet (HFD). Striatal DA, D2Rs, or D2-MSNs are involved in eating behavior (17, 21, 22) and locomotor activity (16, (23) (24) (25) . Systemic or constitutive manipulations of D2Rs modulate energy expenditure (26) as well as brown adipose tissue (BAT) thermogenesis (27) , a mechanism that is gaining increasing interest with respect to energy-balance regulation (28, 29). Thus, due to the potential multimodal effects of D2Rs on metabolism, we examined all sides of the energybalance equation. Finally, because developmental processes may play an important role in obesity etiology (30), and based on the established role of D2Rs in development (31-34), we also determined whether D2R up-regulation restricted to development was sufficient to modulate BW-gain susceptibility. Significance The need to understand the early determinants for obesity has never been greater with currently over 700 million obese people worldwide. Several decades of research have suggested that dopamine 2 receptors (D2R) in the striatum might be particularly important for obesity etiology, but no study has thus far outlined an unambiguous causal relationship. Here we show that striatal D2R upregulation induces obesity in mice fed a high-fat diet and this is due to reduced energy expenditure rather than increased eating. Importantly, we show that elevated D2R during development is sufficient to persistently increase obesity susceptibility. This work identifies excess D2Rs early in life as a potential key predisposition factor toward obesity and therefore may help uncover strategies for early interventions.