GDF15, is a divergent TGF-b superfamily cytokine, most closely related to the GDNFs, that is involved in several processes including energy homoeostasis, inflammatory diseases and cancer. When markedly overproduced in some disease states, such as advanced cancer, it causes an anorexia/cachexia syndrome mediated at least in large part by its actions on appetite control centres in the brain. GDF15 gene knockout mice have a mild obese phenotype, and transgenic overexpressing mice are lean and with improved glucose and insulin tolerance due to reduced energy intake and increased energy expenditure. Drugs based on recombinant GDF15 protein could be a potential therapeutic for obesity and obesity-related complications.
In order to understand the potential efficacy of GDF15 in the treatment of obesity, we infused diet-induced obese and normal mice with recombinant murine GDF15 (0.5 μg/gBW/day) for 28 days and compared the metabolic profiles between the two groups during and at the end of the treatment period. Treatment with GDF15 substantially reduced body weight in both obese and normal mice, largely due to reduced energy intake of about 13-15% that was similar in both groups. The reduction of body weight in obese mice was about 63% greater than in normal mice and was accompanied by a significantly greater (40%) reduction in fat mass, but no reduction in lean mass, compared to that of normal mice. GDF15-treated normal but not obese mice lost lean as well as fat mass. GDF15 treatment reduced circulating levels of pro-inflammatory mediator and adipose tissue and hepatic inflammation in obese mice to a similar level to that of vehicle treated normal mice. It also markedly improved the insulin and glucose intolerance in both obese and normal mice.
GDF15 preferentially reduces fat mass over lean mass in diet-induced obese mice, and effectively corrected the pro-inflammatory metabolic abnormalities that frequently accompany obesity, suggesting it may be a potential therapeutic for obesity.