Responsabile: dott.ssa Stella Bernardi
Background and Significance
Prevalence of obesity with its associated diseases has reached epidemic proportions and its management has become a major public health challenge. New therapies against obesity are desperately needed.
TNF-related apoptosis-inducing ligand (TRAIL) is a soluble protein that induces apoptosis in transformed cells through activation of specific death receptors. In non-transformed cells, however, the actions of TRAIL are less well characterized. Recent studies suggest that TRAIL may have an important role in the treatment of obesity and its associated metabolic disturbances. High-fat diet (HFD) fed TRAIL-knockout mice display significant weight gain as compared to control mice (Di Bartolo, 2011). Consistent with this, we have shown that TRAIL delivery significantly reduces fat gain in HFD fed mice (Bernardi, 2012). In this study, TRAIL significantly increased fatty acid muscular oxidation, improving insulin sensitivity and reducing the levels of
glucose and insulin. Given that altered fatty acid metabolism is involved in the development of obesity, our data suggests that TRAIL reduces weight gain by increasing fatty acid oxidation. Nevertheless, its mechanisms of action remain to be defined. The present application proposes to characterize the mechanisms underlying TRAIL effects on body weight and metabolism, and to study the relationship between TRAIL and conditions stimulating weight loss and lipid oxidation, such as hyperthyroidism and metformin treatment.
Aim 1: To determine: (i) TRAIL effects on adipocyte differentiation and apoptosis, (ii) TRAIL targets on cells involved in lipid metabolism, such as adipocytes, hepatocytes, and myocytes.
Aim 2: To determine the relationship between TRAIL and thyroid hormones and whether TRAIL mediates and/or promotes thyroid hormones peripheral effects.
Aim 3: To determine the relationship between TRAIL and metformin and whether TRAIL mediates and/or promotes metformin peripheral effects.
Hypothesis: TRAIL prevents fat gain not only by inhibiting adipocyte differentiation and promoting adipocyte apoptosis, but also by promoting fatty acid oxidation. TRAIL is upregulated by hormones and drugs that induce weight loss and fatty acid oxidation and it mediates/facilitates part of their peripheral effects.
Impact and Translational Implications
Based on our preliminary findings we expect to clarify whether TRAIL actions on body weight can be ascribed to its effects on adipocyte differentiation and/or apoptosis. Moreover, we expect to understand how TRAIL regulates lipid metabolism, whereby it possibly mediates thyroid hormones/metformin effects. These results will shed light on the mechanisms underlying TRAIL anti-adipogenic effects and open new therapeutic possibilities against weight gain, obesity, and its associated diseases.