Insulin resistance is a key pathological feature of type 2 diabetes and is characterized by defects in signaling by the insulin receptor (IR) protein tyrosine kinase. The inhibition of protein ...tyrosine phosphatases (PTPs) that antagonize IR signaling may provide a means for enhancing the insulin response and alleviating insulin resistance. The prototypic phosphotyrosine‐specific phosphatase PTP1B dephosphorylates the IR and attenuates insulin signaling in muscle and liver. Mice that are deficient for PTP1B exhibit improved glucose homeostasis in diet and genetic models of insulin resistance and type 2 diabetes. The phosphatase TCPTP shares 72% catalytic domain sequence identity with PTP1B and has also been implicated in IR regulation. Despite their high degree of similarity, PTP1B and TCPTP act together in vitro and in vivo to regulate insulin signaling and glucose homeostasis. This review highlights their capacity to act specifically and nonredundantly in cellular signaling, describes their roles in IR regulation and glucose homeostasis, and discusses their potential as drug targets for the enhancement of IR phosphorylation and insulin sensitivity in type 2 diabetes.
PTP1B and TCPTP are closely related classical tyrosine‐specific protein tyrosine phosphatases (PTPs). In this review I will highlight their capacity to act specifically and non‐redundantly in cellular signaling, describe their roles in insulin signaling and glucose homeostasis, and discuss their potential as drug targets for the enhancement of insulin receptor phosphorylation and insulin sensitivity in type 2 diabetes.
Reactive oxygen species (ROS) contribute to the progression of various human diseases, including type 2 diabetes mellitus (T2DM). ROS can suppress the insulin response and contribute to the ...development of insulin resistance, a key pathological feature of T2DM. Paradoxically, ROS generated by NADP(H) oxidases at the plasma membrane and endomembranes might also be required for normal intracellular signaling. Growth factors, cytokines and hormones such as insulin promote the generation of ROS for the coordinated inactivation of protein tyrosine phosphatases and the promotion of tyrosine phosphorylation-dependent signaling. A recent study has established the potential of H2 O2 to enhance insulin sensitivity in vivo and attenuate the development of insulin resistance. Thus, ROS have the capacity to both promote and attenuate the insulin response. Here I review evidence indicating that ROS promote insulin sensitivity versus insulin resistance and discuss the potential complications associated with the widespread use of antioxidants.
The hypothalamus is critical to the coordination of energy balance and glucose homeostasis. It responds to peripheral factors, such as insulin and leptin, that convey to the brain the degree of ...adiposity and the metabolic status of the organism. The development of leptin and insulin resistance in hypothalamic neurons appears to have a key role in the exacerbation of diet-induced obesity. In rodents, this has been attributed partly to the increased expression of the tyrosine phosphatases Protein Tyrosine Phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP), which attenuate leptin and insulin signaling. Deficiencies in PTP1B and TCPTP in the brain, or specific neurons, promote insulin and leptin signaling and prevent diet-induced obesity, type 2 diabetes mellitus (T2DM), and fatty liver disease. Although targeting phosphatases and hypothalamic circuits remains challenging, recent advances indicate that such hurdles might be overcome. Here, we focus on the roles of PTP1B and TCPTP in insulin and leptin signaling and explore their potential as therapeutic targets.
It is now well established that the members of the PTP (protein tyrosine phosphatase) superfamily play critical roles in fundamental biological processes. Although there has been much progress in ...defining the function of PTPs, the task of identifying substrates for these enzymes still presents a challenge. Many PTPs have yet to have their physiological substrates identified. The focus of this review will be on the current state of knowledge of PTP substrates and the approaches used to identify them. We propose experimental criteria that should be satisfied in order to rigorously assign PTP substrates as bona fide. Finally, the progress that has been made in defining the biological roles of PTPs through the identification of their substrates will be discussed.
The primary task of white adipose tissue (WAT) is the storage of lipids. However, “beige” adipocytes also exist in WAT. Beige adipocytes burn fat and dissipate the energy as heat, but their abundance ...is diminished in obesity. Stimulating beige adipocyte development, or WAT browning, increases energy expenditure and holds potential for combating metabolic disease and obesity. Here, we report that insulin and leptin act together on hypothalamic neurons to promote WAT browning and weight loss. Deletion of the phosphatases PTP1B and TCPTP enhanced insulin and leptin signaling in proopiomelanocortin neurons and prevented diet-induced obesity by increasing WAT browning and energy expenditure. The coinfusion of insulin plus leptin into the CNS or the activation of proopiomelanocortin neurons also increased WAT browning and decreased adiposity. Our findings identify a homeostatic mechanism for coordinating the status of energy stores, as relayed by insulin and leptin, with the central control of WAT browning.
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•Insulin and leptin act synergistically on POMC neurons to promote WAT browning•Increased POMC-mediated WAT browning prevents diet-induced obesity•PTP1B and TCPTP attenuate leptin and insulin signaling in POMC neurons•Combined PTP1B and TCPTP deficiency in POMC neurons promotes white fat browning
Insulin and leptin act synergistically in POMC neurons in the hypothalamus to promote white fat browning, increasing thermogenesis and thereby contributing to maintaining energy homeostasis.
The inhibition of protein tyrosine phosphatases 1B (PTP1B) and N2 (PTPN2) has emerged as an exciting approach for bolstering T cell anti-tumor immunity. ABBV-CLS-484 is a PTP1B/PTPN2 inhibitor in ...clinical trials for solid tumors. Here we have explored the therapeutic potential of a related small-molecule-inhibitor, Compound-182. We demonstrate that Compound-182 is a highly potent and selective active site competitive inhibitor of PTP1B and PTPN2 that enhances T cell recruitment and activation and represses the growth of tumors in mice, without promoting overt immune-related toxicities. The enhanced anti-tumor immunity in immunogenic tumors can be ascribed to the inhibition of PTP1B/PTPN2 in T cells, whereas in cold tumors, Compound-182 elicited direct effects on both tumor cells and T cells. Importantly, treatment with Compound-182 rendered otherwise resistant tumors sensitive to α-PD-1 therapy. Our findings establish the potential for small molecule inhibitors of PTP1B and PTPN2 to enhance anti-tumor immunity and combat cancer.
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.
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•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.
Nonalcoholic steatohepatitis (NASH) is triggered by hepatocyte death through activation of caspase 6, as a result of decreased adenosine monophosphate (AMP)-activated protein kinase-alpha (AMPKα) ...activity. Increased hepatocellular death promotes inflammation which drives hepatic fibrosis. We show that the nuclear-localized mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in NASH patients and in NASH diet fed male mice. The focus of this work is to investigate whether and how MKP1 is involved in the development of NASH. Under NASH conditions increased oxidative stress, induces MKP1 expression leading to nuclear p38 MAPK dephosphorylation and decreases liver kinase B1 (LKB1) phosphorylation at a site required to promote LKB1 nuclear exit. Hepatic deletion of MKP1 in NASH diet fed male mice releases nuclear LKB1 into the cytoplasm to activate AMPKα and prevents hepatocellular death, inflammation and NASH. Hence, nuclear-localized MKP1-p38 MAPK-LKB1 signaling is required to suppress AMPKα which triggers hepatocyte death and the development of NASH.
Insulin action in the hypothalamus results in the suppression of hepatic glucose production (HGP). Obesity is often associated with a diminished response to insulin, leading to impaired suppression ...of HGP in obese mice. Here, we demonstrate that blocking central leptin signaling in diet-induced obese (DIO) mice restores the liver’s ability to suppress glucose production. Leptin increases the expression of the insulin receptor phosphatase PTP1B, which is highly expressed in the hypothalamus of DIO mice. We demonstrate that the central pharmacological inhibition or ARH-targeted deletion of PTP1B restores the suppression of HGP in obese mice. Additionally, mice that lack PTP1B in AgRP neurons exhibit enhanced ARH insulin signaling and have improved glucose tolerance and insulin sensitivity. Overall, our findings indicate that obesity-induced increases in PTP1B diminish insulin action in the hypothalamus, resulting in unconstrained HGP and contributing to hyperglycemia in obesity.
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•Antagonizing LepRb restores insulin-mediated suppression of HGP in DIO mice•PTP1B deletion in the ARH of obese mice restores the suppression of HGP•PTP1B deletion in AgRP neurons improves glucose homeostasis in lean and obese mice
Balland et al. identify a molecular link between obesity and type 2 diabetes by demonstrating that, in obesity, leptin signaling in the CNS impairs the regulation of hepatic glucose production, leading to hyperglycemia.
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