Obesity increases the risk of developing metabolic conditions, and primarily type 2 diabetes. The molecular mechanisms by which obesity predisposes people to the development of insulin resistance are so far poorly understood. By deciphering how the protein PTPR-γ, which is increased in obesity, inhibits insulin receptors located at the surface of liver cells, the scientists open the door to potential news therapeutic strategies.
The expansion of fat cells, a characteristic of obesity, leads to an increase in inflammatory signals that have effects on the liver as well as on several other organs. Obesity-induced inflammation triggers the activation of a transcription factor called NF-kβ, which seems to be instrumental in the development of diabetes. Researchers examined various human cohorts-these human studies indicated that PTPR-γ content in liver increases upon inflammation, an effect that could directly affect insulin receptors by inhibiting insulin action.
The scientists modified the levels of PTPR-γ expression in mice, by either suppressing, normally expressing or overexpressing it, and observed the effect on insulin resistance. The mice totally lacking PTPR-γ, when put on a high-calorie diet, did develop obesity. But they did not show any sign of insulin resistance and seemed to be entirely protected from diet-induced diabetes. They also administered lipopolysaccharide, a toxin pertaining to certain bacteria of the gut microbiota associated with obesity and insulin resistance. Once again, the animals lacking PTPR-γ did not develop insulin resistance.
They reconstituted the expression of PTPR-γ at normal levels, but only in hepatocytes (liver cells ). The mice were again prone to insulin resistance, indicating the pivotal role of the liver. Moreover, a two-fold overexpression in the liver (mimicking the natural pathophysiology of obesity was sufficient to cause insulin resistance. The metabolic functions of this protein were never characterized; this discovery therefore opens the door for potential new therapies.
The very form of this protein allows for potential inhibition strategies: when two independent PTPR-γ molecules are brought together by a ligand, they cannot act any more. The researchers are now working on identifying the endogenous ligand produced by the body, or on developing molecules that could mimic its function.
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