Regulation of leptin and insulin signaling by the t cell protein tyrosine phosphatase

The prevalence of obesity and diabetes are increasing at alarming rates. Both are major health concerns worldwide. Food intake, energy expenditure and hepatic glucose production are regulated by hypothalamic neuronal circuits that respond to peripheral signals including leptin and insulin. Leptin is produced by adipose tissue and acts in the hypothalamus via the JAK2/STAT3 signaling pathway to decrease food intake and increase energy expenditure. It is now also widely appreciated that insulin acts in the hypothalamus to control whole body glucose homeostasis, particularly hepatic glucose production. A key negative regulator of leptin and insulin signaling is the protein tyrosine phosphatase 1B (PTP1B). Hypothalamic PTP1B levels are increased in obese and diabetic models and this is thought to contribute to the development of central leptin and insulin resistance. Neuronal or POMC neuron-specific PTP1B deficiency enhances leptin sensitivity and protects mice from the development of diet-induced obesity whereas PTP1B deficiency in liver and muscle enhances insulin sensitivity through enhanced IR phosphorylation. T-cell protein tyrosine phosphatase (TCPTP) is closely related to PTP1B, sharing a high degree of primary and tertiary structural similarity. Several studies have demonstrated that TCPTP dephosphorylates the IR to attenuate insulin signaling in vitro and in vivo in the liver. Moreover, it has been shown that STAT3, a downstream target of leptin receptor signaling, is a TCPTP substrate in the context of the cell cycle and the control of hepatic gluconeogenesis. However, whether TCPTP may regulate leptin and insulin signaling in the brain remains unknown. Thus, the primary objective of this thesis was to examine the potential role of TCPTP in the regulation of central leptin and insulin signaling. The role of TCPTP in the regulation of central leptin signaling was investigated through the generation and characterisation of neuronal cell-specific TCPTP-deficient mice. Work in this thesis demonstrates that TCPTP is a negative regulator in leptin signaling and that TCPTP dephosphorylates and inactivates STAT3 to attenuate leptin signaling. It was shown that hypothalamic TCPTP levels are increased in obesity consistent with TCPTP contributing to the development of leptin resistance and obesity. Moreover, mice that lack both PTP1B and TCPTP in neuronal cells exhibit additive effects in the attenuation of leptin resistance and diet-induced obesity. Therefore, I propose that elevated hypothalamic PTP1B and TCPTP expression in obesity may together contribute to the development of central leptin resistance. In addition, the role of TCPTP in the regulation of central insulin signaling for the control of hepatic glucose metabolism was assessed through the generation of POMC-neuron specific TCPTP-deficient mice. Mice that lack of TCPTP in POMC neurons exhibit enhanced central insulin signaling coinciding with decreased hepatic glucose production and improved whole body insulin sensitivity. Taken together, the results in this thesis define TCPTP as a negative regulator of central leptin and insulin signaling and highlight the capacity for two phosphatases, TCPTP and PTP1B, to work in concert for the regulation of hormonal signaling in a complex neuronal circuit