Human-relevant Ptpn6 mutation alters immune and hepatic functions during aging

Although its functions in immune cells and insulin-responsive tissues are separately established, its integrative function in immunometabolic regulation remains unclear. A damaging variant in the PTPN6 gene (Ala455Thr) was discovered in a French-Canadian family and found to be the cause of early-onset emphysema.

Using mice carrying this whole-body human-relevant mutation, we studied immunometabolic phenotypes across aging. Old mutant mice showed decreased body, liver and adipose tissue weights, improved glucose tolerance, and enhanced hepatic insulin sensitivity. Despite improved metabolic parameters, aged mutant mice developed liver abnormalities, including increased fibrosis and aberrant immune cell infiltration.