TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] is in clinical trials for the treatment of cancer. In the present issue of Clinical Science, Bernardi and co-workers report that the administration of TRAIL in mice fed on a high-fat diet resulted in reduced adiposity and improved metabolic responses to a glucose and insulin tolerance test compared with mice without TRAIL. The metabolic improvements were associated with a higher rate of apoptotic fat cells and with a reduction in the levels of pro-inflammatory cytokines. These results suggest that TRAIL could be an exciting new therapeutic for treating obesity, but further studies are required to determine its major mechanisms of action.
Obesity has reached epidemic proportions worldwide. Obesity is an increasingly important health problem, as it is a major risk factor for insulin resistance, T2DM (Type 2 diabetes mellitus) and cardiovascular diseases . Current therapies for T2DM improve glycaemic control by increasing insulin levels, either directly (exogenous insulin) or indirectly [sulfonylurea derivatives, GLP-1 (glucagon-like peptide-1) analogues and DPP-4 (dipeptidyl peptidase-4) inhibitors] or by improving insulin sensitivity (biguanides and thiazolidinediones). Agents that target the primary cause of T2DM, i.e. obesity, are presently non-existent, but the study by Bernardi and co-workers  in the present issue of Clinical Science suggest that TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] may have some potential.
TRAIL, a member of the TNF-α cytokine family, induces apoptosis via the extrinsic apoptotic pathway and a cross-talk between intrinsic and extrinsic pathways. It preferentially promotes apoptosis in transformed cells and is therefore most well known as an anticancer agent . Previously, TRAIL has been shown to also reduce atherosclerosis and ameliorate T1DM (Type 1 diabetes mellitus) and T2DM [4–6]. TRAIL blockade in non-obese diabetic mice, as well as TRAIL deficiency in mice with streptozotocin-induced T1DM, resulted in an exacerbation of diabetes and in an increase in autoimmune inflammation in pancreatic islets . In accordance with these results, administration of TRAIL improved streptozotocin-induced T1DM . This positive metabolic effect is most probably caused by an attenuated autoimmune response through TRAIL-induced apoptosis of macrophages and T-cells [5,6]. To date, only one study has investigated the effects of TRAIL on T2DM . In that study, the increase in body weight and glucose intolerance after a high-fat diet for 12 weeks was larger in TRAIL−/−/ApoE (apolipoprotein)−/− mice and in TRAIL−/− mice compared with ApoE−/− mice. These features were associated with reduced insulin levels and pancreatic inflammation .
In the present issue of Clinical Science, Bernardi and co-workers  are the first to report the effects of TRAIL administration in mice with insulin resistance induced by a high-fat diet, which is the most widely accepted model of human obesity. After a high-fat diet, adiposity in C57bl6 mice treated with TRAIL for 12 weeks was reduced compared with mice without TRAIL. Moreover, TRAIL-treated mice had a reduction in hyperglycaemia and hyperinsulinaemia during a glucose tolerance test and had an improved response to insulin during an insulin tolerance test compared with mice without TRAIL. TRAIL further increased skeletal muscle fatty acid oxidation. The metabolic improvements were associated with a higher rate of apoptotic fat cells and with a decrease in the plasma and tissue (fat, liver and skeletal muscle) levels of the pro-inflammatory cytokines IL (interleukin)-6, TNF-α and MCP-1 (monocyte chemoattractant protein-1).
The authors hypothesized that TRAIL reduces adiposity by inducing adipocyte apoptosis, which in turn may result in reduced inflammation and eventually in the positive metabolic effects. TRAIL has been described to preferentially promote apoptosis in transformed cells ; however, recently, TRAIL has been reported to be pro-apoptotic in human subcutaneous pre-adipocytes as well . Unfortunately, Bernardi and co-workers  did not describe whether apoptosis was induced in visceral fat, subcutaneous fat or both. Neither do they report where body fat mass was reduced. This is important as particularly visceral fat accumulation results in metabolic disturbances . Therefore a reduction in visceral fat mass could be very beneficial. In contrast, a decrease in subcutaneous fat could affect glucose metabolism in a negative way, as shown in patients with congenital or HIV lipoatrophy . Other explanations for the loss of fat should also be considered. In particular, mice treated with TRAIL had much greater locomotor activity compared with mice without TRAIL, and this was associated with a tendency for greater energy expenditure. In addition to the greater locomotor activity, weight loss could also be due to a direct effect of TRAIL on increasing the activity of brown adipose tissue or increasing the conversion of white adipocytes into more energetically active brite (brown-in-white) or beige adipocytes.
Cellular fatty acid metabolism and inflammation are intimately linked . In the present study , both reductions in inflammation and increases in skeletal muscle fatty acid oxidation were detected, but it was not clear whether this was a direct effect of TRAIL or was secondary to weight loss. Future studies examining acute effects of TRAIL on both inflammation and fatty acid metabolism will be important for understanding its mechanism of action. As previous studies have shown that the reduction in inflammation can result from a direct anti-inflammatory effect of TRAIL through the induction of macrophage and T-cell apoptosis [5,6], the elimination of inflamed adipose tissue macrophages may be an important mode of action. Apart from influencing insulin sensitivity by diminishing inflammation, TRAIL may have also improved glucose homoeostasis through direct effects on the insulin signalling pathway via activation of PKB (protein kinase B)/Akt .
In future studies, the exact mechanisms by which TRAIL induces weight loss and improves insulin sensitivity will need to be elucidated. In particular, a specific emphasis on completing more extensive analysis of body composition, adipocyte differentiation and energy expenditure will be important. Additionally, the investigation of the metabolic effects of TRAIL on fatty acid metabolism and macrophage inflammation may also be very revealing to its mode of action. However, as TRAIL has proven to be safe and well tolerated in human cancer patients , further studies examining the metabolic effects in obese humans will ultimately determine whether this novel therapy may be effective in treating obesity and its related complications.