PTP1B deficiency in the reward system suppressed the rewarding value of a high-fat diet

Insulin and leptin signaling in dopaminergic neurons (DNs) of the ventral tegmental area and their projection targets, corticostriatal neurons (CSNs), are known to suppress hedonic feeding. However, the role of protein tyrosine phosphatase 1B (PTP1B), a negative regulator of these pathways, in reward-driven eating remains unclear. Here, we generated DN- and CSN-specific PTP1B knockout mice (D-KO and CS-KO, respectively) using the Cre-loxP system. In a conditioned place preference test, wild-type (WT) mice exhibited high-fat diet (HFD)-induced place preference, whereas D-KO and CS-KO mice did not. Binge-like feeding behavior induced by intermittent access to a HFD was attenuated in female D-KO and CS-KO mice. Body weight, glucose tolerance, and insulin tolerance did not differ significantly among groups. These findings indicate that PTP1B deficiency in DNs and CSNs suppresses the rewarding value of a HFD without altering energy balance or glucose metabolism.