Dopamine Neuron–Restricted Leptin Receptor Signaling Reduces Some Aspects of Food Reward but Exacerbates the Obesity of Leptin Receptor–Deficient Male Mice

The contribution of leptin-induced modulation of dopamine neurons to feeding behavior and energy homeostasis remains unclear. Midbrain dopamine neurons regulate the reward value of food, and direct leptin administration to the midbrain reduces food intake. However, selective deletion of leptin receptors (Leprs) from dopamine neurons has no effect on body weight, food intake, or hedonic responses, suggesting that leptin acts indirectly or demonstrating that sufficient compensation occurs to mask any direct leptin–dopamine effects. To further explore the role of direct Lepr–dopamine neuron signaling in the control of feeding behavior and energy homeostasis, we generated mice in which Leprs were expressed exclusively in dopamine transporter (DAT)–expressing neurons (LeprDAT). We then assessed weekly body weight, daily food intake, hyperphagic feeding, and leptin-induced suppression of feeding in the LeprDAT mice compared with their Lepr-deficient (LeprNULL) and wild-type control (LeprCON) littermates. We also used metabolic cages to characterize running wheel activity, home-cage activity, and total energy expenditure. As expected, LeprNULL mice exhibited increased body weight and food intake compared with LeprCON mice. LeprDAT male mice exhibited acute leptin-induced suppression of food intake and reduced hedonic feeding but also exhibited significantly increased postweaning body weight gain compared with the LeprNULL mice. This was associated with significantly reduced home-cage activity counts, although no differences in food intake were observed between the LeprDAT and LeprNULL mice. These data demonstrate that restoring Lepr signaling exclusively in dopamine neurons reduces some aspects of food reward and activity but does not ameliorate the obesity phenotype of Lepr-deficient mice.In mice with leptin receptor expression restricted to dopamine neurons, leptin–dopamine signaling is sufficient to reduce some aspects of food reward and activity, but the obesity phenotype persists.