TNF-related apoptosis-inducing ligand significantly attenuates metabolic abnormalities in high fat fed mice reducing adiposity and systemic inflammation.

Aims/hypothesis: Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) has recently been shown to ameliorate the natural history of diabetes mellitus (DM). It has not been determined yet whether systemic TRAIL delivery would prevent the metabolic abnormalities due to a high fat diet (HFD). Methods: For this purpose 27 male mice C57bl6 aged 8 weeks were randomly allocated to standard diet, HFD or HFD + TRAIL for 12 weeks. TRAIL was delivered weekly by intra-peritoneal injection. Body composition was evaluated; indirect calorimetry studies, glucose tolerance test (GTT) and insulin tolerance tests (ITT) were performed. Pro-inflammatory cytokines together with adipose tissue gene expression and apoptosis were measured. Results: TRAIL treatment reduced significantly the increased adiposity associated with a HFD. Moreover, it reduced significantly hyperglycaemia and hyperisulinemia during a GTT and it improved significantly the peripheral response to insulin. TRAIL reversed the changes in substrate utilization induced by HFD and ameliorated skeletal muscle free fatty acids oxidation rate. This was associated with a significant reduction of pro-inflammatory cytokines together with a modulation of adipose tissue gene expression and apoptosis. Conclusions: This data sheds light on the possible anti-adipogenic and anti-inflammatory effects of TRAIL and opens new therapeutic possibilities against obesity, systemic inflammation and type 2 DM.