Osteopontin knockout abates high fat diet-induced insulin resistance and adipose tissue inflammation

In recent years type 2 diabetes has been shown to consist of not only insulin resistance of insulin target tissues (muscle, adipose tissue, and liver) but inflammation of adipose tissue as well. This inflammatory state is characterized by increased macrophage infiltration and pro -inflammatory cytokine expression. Given the known pro- inflammatory roles of osteopontin in many pathological states in addition to its cell migration enhancing properties, osteopontin was examined for its effect on diet-induced obesity. Osteopontin knockout mice exhibited increased liver insulin sensitivity by hyperinsulinemic euglycemic clamp after two and 16 weeks on high fat diet compared to the wild type mice. Increased muscle insulin sensitivity was also observable after two weeks on diet by clamp in the knockout mice. Enhanced insulin signaling in muscle, adipose tissue, and liver, assessed by Akt phosphorylation, was also observed in the osteopontin knockout mice versus the wild type mice after high fat feeding, indicating attenuated insulin resistance. Osteopontin knockout mice also showed diminished adipose tissue hypertrophy, triple-positive pro-inflammatory cell infiltration into adipose tissue, and inflammatory cytokine expression, indicating less inflammation of the adipose tissue after short-term high fat diet. Total osteopontin expression as well as differential isomeric expression of it in the adipose tissue was observed to increase after high-fat diet in wild type mice, further implicating its role in inflammation of the adipose tissue. Osteopontin appears to mediate the effects of short- and long-term diet-induced obesity in a cytokine- like manner, leading to localized inflammation of the adipose tissue which results in systemic insulin resistanc