Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin receptor signalling and may contribute to leptin resistance in diet-induced obesity. Although PTP1B inhibition has been suggested as a potential weight loss therapy, the role of specific neuronal PTP1B signalling in cardiovascular and metabolic regulation and the importance of sex differences in this regulation are still unclear. In this study, we investigated the impact of pro-opiomelanocortin (POMC) neuronal PTP1B deficiency in cardiometabolic regulation in male and female mice fed a high fat diet (HFD). Compared to control mice (PTP1Bflox/flox), male and female mice deficient in POMC neuronal PTP1B (PTP1Bflox/flox/POMC-Cre) had attenuated body weight gain (Male: -18%; Fem ale: -16%) and fat mass (Male: -33%; Female: -29%) in response to HFD. Glucose tolerance was improved by 40% and liver lipid accumulation was reduced by 40% in PTP1Bflox/flox/POMC-Cre males but not in females. Compared to control mice, deficiency of POMC neuronal PTP1B did not alter mean arterial pressure (MAP) in male or female mice (Male: 112{plus minus}1 vs. 112{plus minus}1 mmHg in controls; Female: 106{plus minus}3 vs. 109{plus minus}3 mmHg in controls). Deficiency of POMC neuronal PTP1B also did not alter MAP response to acute stress in male or female compared to control mice (Male: Δ32{plus minus}0 vs. Δ29{plus minus}4 mmHg; Female: Δ22{plus minus}2 vs. Δ27{plus minus}4 mmHg). These data demonstrate that POMC-specific PTP1B deficiency improved glucose tolerance and attenuated diet-induced fatty liver only in male mice, attenuated weight gain in males and females, but did not enhance the MAP and HR responses to a HFD or to acute stress.