Scientists have identified a potentially key role for tyrosine phosphatase epsilon (RPTPe) in the mechanisms involved in obesity, glucose regulation, and leptin sensitivity. The research team, led by the Weizmann Institute’s Ari Elson, Ph.D., has found that female mice lacking RPTPe are protected from the weight gain that normally occurs either as a result of a high-fat diet (HFD), ovariectomy, or aging.
They also found that the female RPTPe knockouts (EKOs) demonstrated increased leptin sensitivity, even in the obese state, while EKO mice of both genders exhibited improved response to glucose load. The animal studies are reported in Cell Metabolism in a paper titled “Protein Tyrosine Phosphatase Epsilon Affects Body Weight by Downregulating Leptin Signaling in a Phosphorylation-Dependent Manner.”
Binding of leptin to its receptor in the hypothalamus activates the JAK2 tyrosine kinase, which leads to phosphorylation of the receptor and activation of downstream signaling, Dr. Elson and colleagues explain. The importance of tyrosine phosphorylation in regulating leptin receptor signaling suggests that protein tyrosine phosphatases that antagonize tyrosine kinase activity could therefore impact body weight. The team tested this hypothesis by breeding mice that genetically lack RPTPe, a phosphatase that downregulates insulin receptor signaling in cells.
The found that at 14–16 months of age, female and male EKO animals weighed significantly less than matched wild-type (WT) controls. When fed a HFD for 11 weeks, the female EKOs, though not the male EKOs, also gained 55% less weight than matched WT controls. While ovariectomy led to WT mice putting on an extra 32% in weight within weeks, ovariectomized EKO animals demonstrated no weight gain.
Protection of EKO mice from weight gain either due to a HFD or ovariectomy was associated with reduced body fat content, the researchers note. High fat diet, ovariectomy, and old age all significantly increased the relative weight of abdominal white fat pads in WT female mice, but in EKO animals this effect was either significantly reduced or completely absent.
Interestingly, EKO mice consumed the same amount of food as their age- and gender-matched WT counterparts. Calorimetric studies showed that when fed regular chow, the EKO mice displayed strong trends toward increased consumption of oxygen, increased CO2 production, and increased heat production. These trends reached clear statistical significance when the mice were fed high fat food.
Female EKO mice fed regular chow also exhibited a very strong trend for reduced circulating leptin concentrations. Levels of circulating leptin in aged, ovariectomized, or high fat-fed WT mice increased significantly, which is consistent with the establishment of a leptin-resistant state. In contrast, leptin concentrations were significantly lower in EKO mice that were similarly challenged.
Fasting concentrations of glucose and insulin were similar in the plasma of WT and EKO mice of both genders that were fed regular chow. Exposing EKO and WT mice to a prolonged HFD significantly increased fasting concentrations of circulating glucose and insulin. However, glucose and insulin concentrations in male EKO mice fed an HFD were markedly reduced relative to WT mice, suggesting insulin hypersensitivity, the authors note.
These findings were also demonstrated in female EKO animals, although to a lesser degree than in males. When challenged with an intraperitoneal glucose load, EKO male mice displayed significantly improved responses when fed regular or high-fat food.
Importantly, molecular studies showed that leptin-induced STAT3 phosphorylation was 38% stronger in EKO hypothalami, confirming the knockout animals’ leptin hypersensitivity. Further analyses strongly suggested that RPTPe inhibits leptin receptor signaling by targeting the downstream kinase JAK2.
The overall findings could have implications for the future treatment of human obesity, the researchers claim. Administration of leptin to obese humans generally fails to reduce body weight due to obesity-induced leptin resistance.
The researchers suggest, however, that “targeted inhibition of those protein tyrosine phosphatases, such as RPTPe, which inhibit leptin receptor signaling and which are important for establishing leptin resistance in the obese state, may increase the usefulness of treating obesity with leptin.”