Liver Link between Obesity and Diabetes Highlights New Therapeutic Target

The strong links between obesity and the development of type 2 diabetes mellitus (T2DM) have long been recognized, but the cellular and molecular mechanisms underpinning that relationship are not yet well understood. An international team of scientists has now found that overexpression of the protein tyrosine phosphatase receptor gamma (PTPR-γ) specifically in the liver acts as the molecular link between obesity-induced inflammation and insulin resistance and could represent a new target for treating T2DM.

The researchers, led by Roberto Coppari, Ph.D., coordinator of the University of Geneva (UNIGE) Faculty of Medicine Diabetes Centre, report on their studies in Nature Communications, in a paper entitled “Hepatic Protein Tyrosine Phosphatase Receptor Gamma Links Obesity-Induced Inflammation to Insulin Resistance.”

An estimated 1.9 billion people globally are now either overweight or obese, the authors note. A major complication of obesity is the increased risk for developing metabolic disorders, particularly T2DM. Inflammation is believed to represent a key link between adiposity and T2DM, and while the mechanisms at work have yet to be defined, scientists have observed that obesity triggers an increase in inflammatory molecules, which activates the transcription factor NF-κB, leading to the development of cellular insulin resistance.

To gain a greater understanding of the molecular pathways that link obesity to T2DM, the UNIGE team, working with colleagues in Switzerland, Japan, the U.S., and France, focused on the expression of PTPR-γ, which is a target of NF-κB. They initially looked at existing human data to see if expression of the PTPR-γ protein was altered in obese individuals. “We first 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,” Prof. Coppari comments.

The researchers next looked more closely at the effects of PTPR-γ expression on insulin resistance by either knocking out or overexpressing the protein in experimental mice. Interestingly, they found that knocking out PTPR-γ didn’t stop the animals from becoming obese when they were fed a high-calorie diet. However, the total lack of PTPR-γ did stop the obese mice from developing insulin resistance. PTPR-γ knockout mice that were fed a high-calorie diet also had much better glucose tolerance compared with control animals. “The mice totally lacking PTPR-γ, when put on a high-calorie diet, did develop obesity, notes Xavier Brenachot, Ph.D., a researcher at UNIGE Faculty of Medicine and first author of the researchers’ published study. “But they did not show any sign of insulin resistance and seemed to be entirely protected from diet-induced diabetes.”

Subsequent analyses suggested that a lack of PTPR-γ improved glucose homeostasis, at least in part, by boosting hepatic insulin sensitivity. So, to investigate the role of the liver more closely, the team re-expressed PTPR-γ in the knockout mice, but only in the animals’ livers. They found that a twofold overexpression of PTPR-γ in the liver, which is effectively the same level of expression that typically occurs in obesity, was enough to cause hepatic insulin resistance. Subsequent studies in cell lines also suggested that PTPR-γ expression as a result of obesity was induced by inflammation via activation of NF-κB.

“In summary, our results indicate that the increased hepatic PTPR-γ level observed in obesity is sufficient to cause insulin resistance and hence unveil PTPR-γ as a new target for anti-T2DM therapy,” the authors wrote. “Our data suggest that means aimed at decreasing hepatic PTPR-γ expression/activity should improve T2DM. This goal could be achieved by development of specific PTPR-γ inhibitors.”

Previous studies have already focused on PTP proteins as potential treatments for diabetes. But, while many of this family are intracellular proteins, PTPR-γ is located in the cell membrane and so could represent a more accessible and promising therapeutic target. Structural studies have also suggested that PTPR-γ exists as both an active monomer and an inactive homodimer, which is generated when the protein binds to its endogenous ligand. “Several members of the contactin family have been suggested as endogenous PTPR-γ ligands,” the researchers note. “Hence, experiments aimed at testing whether these ligands inhibit PTPR-γ and improve T2DM are warranted.” The team is now working to identify the endogenous ligands of PTPR-γ, and look at the potential to develop develop ligands that mimic its function.