Exercise training promotes a GDF15-associated reduction in fat mass in older adults with obesity

Obesity is a major risk factor for metabolic disease. Growth differentiation factor 15 (GDF15) has shown promise as a weight loss agent for obesity in animal studies. In healthy lean humans, fasting plasma GDF15 increases after acute exercise. However, the role of GDF15 in human obesity and the response of plasma GDF15 to exercise training in patients with obesity is unknown. Here, 24 sedentary volunteers with obesity [age: 65 ± 1 yr; body mass index (BMI): 35.3 ± 0.9 kg/m²] participated in a supervised 12-wk aerobic exercise intervention: 1 h/day, 5 days/wk at ~85% maximum heart rate with controlled isocaloric diet. As a result, plasma GDF15 was significantly increased (PRE: 644.1 ± 42.6 pg/ml, POST: 704.4 ± 47.2 pg/ml, P < 0.01) after the exercise intervention. Inconsistent with animal models, ΔGDF15 was not correlated with change in weight, BMI, or resting energy expenditure. However, ΔGDF15 was correlated with a reduction in total fat mass (P < 0.05), abdominal fat mass (P < 0.05), and android fat mass (P ≤ 0.05). Participants with a positive GDF15 response to exercise had increased total fat oxidation (PRE: 0.25 ± 0.05 mg·kg^-1·min^-1, POST: 0.43 ± 0.07 mg·kg^-1·min^-1, P ≤ 0.05), metabolic flexibility [PRE: -0.01 ± 0.01 delta respiratory quotient (RQ), POST: 0.06 ± 0.01 delta RQ, P < 0.001], and insulin sensitivity (PRE: 0.33 ± 0.01 QUICKI index, POST: 0.34 ± 0.01 QUICKI index, P < 0.01), suggesting a link between GDF15 and fat mass loss as well as exercise-induced metabolic improvement in humans with obesity. We conclude that the exercise-induced increase in plasma GDF15 and the association with reduced fat mass may indicate a role for GDF15 as a therapeutic target for human obesity.