The importance of hypothalamic leptin and insulin resistance in the development and maintenance of obesity remains unclear. The tyrosine phosphatases protein tyrosine phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP) attenuate leptin and insulin signaling and are elevated in the hypothalami of obese mice. We report that elevated PTP1B and TCPTP antagonize hypothalamic leptin and insulin signaling and contribute to the maintenance of obesity. Deletion of PTP1B and TCPTP in the hypothalami of obese mice enhances CNS leptin and insulin sensitivity, represses feeding, and increases browning, to decrease adiposity and improve glucose metabolism. The daily intranasal administration of a PTP1B inhibitor, plus the glucocorticoid antagonist RU486 that decreases TCPTP expression, represses feeding, increases browning, promotes weight loss, and improves glucose metabolism in obese mice. Our findings causally link heightened hypothalamic PTP1B and TCPTP with leptin and insulin resistance and the maintenance of obesity and define a viable pharmacological approach by which to promote weight loss in obesity. Display omitted •Elevated ARC PTP1B and TCPTP contribute to the maintenance of DIO•Deletion of ARC PTP1B and TCPTP in DIO reinstates leptin and insulin sensitivity•Deletion of ARC PTP1B and TCPTP represses feeding and promotes WAT browning in DIO•Intranasal targeting of ARC PTP1B and TCPTP promotes weight loss in DIO Dodd et al. report that in obesity heightened hypothalamic levels of PTP1B and TCPTP repress insulin and leptin responses and contribute to the maintenance of obesity. The combined intranasal targeting of PTP1B and TCPTP increases leptin and insulin sensitivity and promotes weight loss by repressing feeding and increasing energy expenditure.