Effect of growth differentiation factor 15 (GDF-15) inhibition on energy balance in cancer cachexia and in lipopolysaccharide (LPS)-induced sepsis mouse models.

Abstract

e24153 Background: Growth differentiation factor 15 (GDF-15) is a cytokine that induces anorexia, weight loss and has been reported to be associated with cachexia and poor survival in illnesses characterized by inflammation such as cancer cachexia and heart failure. In preclinical cancer cachexia models, GDF-15 inhibition has been demonstrated to reverse cachexia and improve survival. Circulating GDF-15 is also elevated in patients with sepsis and is associated with increased complications and poor survival. However, the role of infection- and sepsis-induced GDF-15 in mouse models is controversial based on published reports. Methods: In this study, we examined the effect of GDF-15 inhibition on tumor and lipopolysaccharide (LPS)-induced anorexia, weight loss, and survival using a GDF-15 neutralizing antibody (mAB2) and GDF-15 knockout mice. Results: mAB2 efficacy was confirmed by reversing AAV-GDF-15-induced weight loss in wildtype mice. A cachectic (anorexia and weight loss) mouse tumor model was established with subcutaneous implantation of mouse renal cell carcinoma (RENCA) cells. The chemotherapy sorafenib was administered to slow tumor progression. Plasma GDF-15 was increased to ~2 ng/mL, similar to levels in cancer patients. Treatment with mAB2 rapidly reversed both anorexia and weight loss in the tumor-bearing mice. LPS injection (intraperitoneal, 5 mg/kg) increased circulating GDF-15 in wildtype mice reaching concentrations like that reported in septic patients within 90 minutes and remaining elevated after 48 hours (~1 ng/mL). LPS decreased food intake, body weight, and increased mortality (~20%). Different from the tumor model, GDF-15 neutralization with mAB2 did not prevent or exacerbate any of the effects of LPS. There were no observed detrimental effects of mAB2 treatment in either model. Similarly, in GDF-15 knockout mice the LPS effect on energy balance and survival was comparable to that observed in wildtype controls. Plasma GDF-15 was undetectable in the GDF-15 knockout mice. Conclusions: Taken together, these data suggest that GDF-15 is a critical regulator of energy balance and survival in selective pathophysiological states associated with weight loss.