The ability of insulin and leptin to reduce reward related behaviors could occur through action at two distinct regions that modulate mesolimbic activity. Tyrosine hydroxylase (TH) neurons in the (VTA) promote feeding and drug taking behavior; these neurons receive a direct connection from orexin neurons located in the lateral hypothalamus (LH) which activates VTA neurons through signaling at the orexin-1 receptor, as indicated by the vertical black lines. This circuit mediates non-homeostatic food consumption and drug relapse behavior. Leptin receptors are present on LH neurons and leptin negatively regulates orexin and orexin-1-receptor gene expression within LH neurons. Moreover, insulin and leptin act upon VTA neurons to negatively regulate dopamine tone and over-consumption of palatable foods as indicated by the green arrows. It is unclear if leptin acting within LH neurons affects arousal, feeding or anticipation of rewards; likewise it is unclear if leptin signaling within VTA neurons affects reward related behaviors. Thus, insulin and leptin may act at two distinct brain regions to modulate mesolimbic signaling and reward related behaviors. VTA: ventral tegmental area, LH: Lateral Hypothalamus.

The ability of insulin and leptin to mediate reward behavior at the molecular level might occur through the activation of insulin receptor substrate (IRS-2) in ventral tegmental area (VTA) neurons. Both insulin and leptin receptors are present on VTA neurons and upon activation, both activate intracellular signaling cascades that ultimately affect gene transcription. Intracellular signaling from both the insulin and leptin receptor converges at IRS-2. IRS-2 signaling regulates the psychostimulant mediated plasticity and reward. Thus, it is possible for insulin and leptin to regulate reward behaviors through their action on IRS-2 in the VTA. It is unclear if insulin and leptin signaling within VTA neurons elicits IRS-2 activation; however, the ability of leptin to negatively regulate food intake behavior is mediated by Jak-2 (Jak-STAT) signaling within VTA neurons. IRS-2: Insulin receptor substrate, VTA: ventral tegmental area, Jak-2: Janus kinase, Jak-STAT: Janus kinase signal transducers and activators of transcription, TH: Tyrosine hydroxylase.