Inflammation is implicated in metabolic abnormalities in
obesity and
type 2 diabetes. Because θ-
defensins have anti-inflammatory activities, we tested whether
RTD-1, a θ-
defensin, improves metabolic conditions in diet-induced
obesity (DIO). DIO was induced by high-fat feeding in obese-prone CD rats from 4 wk of age. Starting at age 10 wk, the DIO rats were treated with saline or
RTD-1 for 4 or 8 wk. DIO rats gained more weight than low-fat-fed controls.
RTD-1 treatment did not alter
body weight or calorie intake in DIO rats. Plasma
glucose, FFA,
triglyceride (TG), and
insulin levels increased in DIO rats;
RTD-1 normalized plasma
glucose and FFA levels and showed tendencies to lower plasma
insulin and TG levels. Hepatic and skeletal muscle TG contents increased in DIO rats;
RTD-1 decreased muscle, but not hepatic, TG content.
Insulin sensitivity, estimated using homeostasis model assessment of
insulin resistance and the
glucose clamp technique, decreased in DIO rats, but this change was markedly reversed by
RTD-1.
RTD-1 had no significant effects on plasma
cytokine/
chemokine levels or IL-1β and TNF-α expression in liver or adipose tissues.
RTD-1 treatment decreased hepatic expression of
phosphoenolpyruvate carboxykinase and
glucose-6-phosphatase, suggesting that the effect of
RTD-1 on plasma
glucose (or
insulin action) might be mediated by its effect to decrease hepatic gluconeogenesis. Thus,
RTD-1 ameliorated
insulin resistance and normalized plasma
glucose and FFA levels in DIO rats, supporting the potential of
RTD-1 as a novel therapeutic agent for
insulin resistance,
metabolic syndrome, or
type 2 diabetes.