Elevated Hypothalamic TCPTP in Obesity Contributes to Cellular Leptin Resistance

In obesity, anorectic responses to leptin are diminished, giving rise to the concept of “leptin resistance.” Increased expression of protein tyrosine phosphatase 1B (PTP1B) has been associated with the attenuation of leptin signaling and development of cellular leptin resistance. Here we report that hypothalamic levels of the tyrosine phosphatase TCPTP are also elevated in obesity to attenuate the leptin response. We show that mice that lack TCPTP in neuronal cells have enhanced leptin sensitivity and are resistant to high-fat-diet-induced weight gain and the development of leptin resistance. Also, intracerebroventricular administration of a TCPTP inhibitor enhances leptin signaling and responses in mice. Moreover, the combined deletion of TCPTP and PTP1B in neuronal cells has additive effects in the prevention of diet-induced obesity. Our results identify TCPTP as a critical negative regulator of hypothalamic leptin signaling and causally link elevated TCPTP to the development of cellular leptin resistance in obesity. [Display omitted] ► Hypothalamic TCPTP is elevated in obesity together with PTP1B and SOCS3 ► TCPTP attenuates leptin-induced STAT3 signaling ► TCPTP deficiency/inhibition enhances leptin sensitivity ► Combined PTP1B/TCPTP deletion has additive effects on leptin sensitivity and obesity