Our evolving understanding of the interaction between leptin and dopamine system to regulate ingestive behaviors

Abstract

Dopamine (DA) has been with us scientifically for a long time. Dopamine's function as a neurotransmitter was first recognized in 1958, a finding that eventually led to Arvid Carlsson being awarded the Nobel Prize in 2000. Among its numerous identified physiological roles, dopaminergic signaling is well known to regulate ingestive behaviors [1]. This is not surprising. Eating food is a pleasurable act and the DA projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) clearly play a role in many aspects of reward that shape behavior. Consequently, a number of investigators have hypothesized a role for the DA system to interact with key peripheral signals that regulate food intake such as leptin [2,3] and ghrelin [4]. Literally thousands of papers have focused on the hypothalamic pathways mediating the anorectic effect of leptin. However, leptin receptors are also expressed in the VTA, and leptin decreases the firing rate of DA neurons and decreases feeding behavior independently of hypothalamic mechanisms [2,3]. In this issue, Billes and colleagues report that the systemic injection of DA receptor 2 antagonists before leptin treatment blunts the anorexigenic action of leptin [5]. Supporting those pharmacological findings, the administration of leptin to mice lacking DA receptor 2 showed an attenuated effect of leptin on feeding [5]. Conversely, DA receptor blockade had no effect on the acute hypophagic effect of melanocortin receptor agonists or the increased food intake caused by exogenous ghrelin administration [5]. This work lays another important brick in the foundation that leptin and the DA system have important interactions that are critical for the regulation of food intake and points the finger squarely at the D2 receptor as a key component of this interaction. This leaves open several interesting questions. First, which neuronal population is responsible for the interaction between leptin and DA receptor 2. Since both leptin and DA receptors are located within the VTA and different hypothalamic nuclei, other methodologies will need to be applied to give us clues as to the key neuroanatomical locations that mediate these effects. This question remains important since a previous study reported that DA receptor 2-deficient mice showed an increased response to central leptin administration [6]. Therefore, it is plausible to hypothesize that the manipulation of DA receptor 2 in specific neuronal populations might differentially affect leptin's actions. A second important question concerns the molecular pathway mediating the interaction between leptin and D2R. It could be hypothesized that the long isoform of the leptin receptor heterodimerizes with D2R. Interestingly, such heterodimers have been identified for ghrelin receptor (GHS-R1a) and D2R, and preventing such heterodimers alters the DRD2 signal transduction [7]. Answering this question could identify potential new downstream targets modulating the anorectic action of leptin. Finally, a key question concerns the possibility that leptin's actions on the DA system impact not only ingestive behaviors but have an important role in a wide range of other behaviors. For example, the dopaminergic system plays an important role as a mediator of the actions of ghrelin on food intake [4], spatial memories [8], and locomotor activity [9]. The findings of Billes et al. highlight the relevance of the dopaminergic system as a physiological mediator of feeding behavior and as a regulator of leptin's actions. Given that this interaction is independent of the melanocortin system it highlights the need to continue to explore new pathways that may underlie leptin's effects on energy balance, reproduction and peripheral fuel utilization. Revealing such pathways allows for new insights that can provide for better understanding of how dysregulation of body weight can occur and novel therapeutic strategies to make it easier for individuals to sustain meaningful weight loss.