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

Abstract

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 (Lepr DAT ). We then assessed weekly body weight, daily food intake, hyperphagic feeding, and leptin-induced suppression of feeding in the Lepr DAT mice compared with their Leprdeficient (Lepr NULL ) and wild-type control (Lepr CON ) littermates. We also used metabolic cages to characterize running wheel activity, home-cage activity, and total energy expenditure. As expected, Lepr NULL mice exhibited increased body weight and food intake compared with Lepr CON mice. Lepr DAT 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 Lepr NULL mice. This was associated with significantly reduced home-cage activity counts, although no differences in food intake were observed between the Lepr DAT and Lepr NULL 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 Leprdeficient mice. (Endocrinology 158: 4246-4256, 2017) F eeding motivation is crucial for an animal's survival, and neural circuits that promote appetite and the drive to seek and consume food have therefore evolved to safeguard against starvation. However, as evidenced by the prevailing obesity epidemic, maladaptive feeding behavior can develop such that an individual's food intake is no longer in balance with his or her energy needs. To identify, and ultimately target, the underlying causes of this maladaptive feeding behavior, we need to enhance our understanding of the neurobiological mechanisms involved in the control of energy homeostasis. Although both hypothalamic and extrahypothalamic brain circuits are known to be involved (1), the interplay between hedonic and hunger-driven feeding responses remains incompletely understood.