GDF15 Induces Weight Loss with Diet- and Age-Dependent Metabolic Effects Across Tissues in Mice.

Growth differentiation factor 15 (GDF15) is a regulator of body weight and systemic homeostasis. However, the mechanisms underlying its effects remain unclear. This study aimed to determine whether diet, age, and sex influence GDF15's metabolic effects. Male and female mice aged 8 or 64 weeks were fed a normal diet (ND) or high-fat diet (HFD) for 20 weeks and were treated subcutaneously with recombinant GDF15 or vehicle for 3 weeks. Body weight and food intake were monitored. Epididymal white adipose tissue (eWAT), subcutaneous WAT (scWAT), brown adipose tissue (BAT), liver, and gastrocnemius muscle were analyzed by histology and gene expression. GDF15 reduced body weight, with greater effects in HFD-fed and aged mice. Reduced food intake was mainly observed in young HFD-fed mice. GDF15 improved glycemic control and exerted tissue-, diet-, and age-dependent effects. The liver showed greater transcriptional changes, especially in aged mice, although GDF15 also induced tissue-specific changes in BAT, gastrocnemius muscle, and eWAT. Gdf15 expression was more strongly induced by HFD in BAT and by aging in eWAT. These findings reveal that GDF15 exerts robust metabolic effects on body weight and glucose homeostasis, with age-dependent effects on food intake. GDF15 induced tissue-specific responses influenced by diet and age that may contribute to its systemic effects. These findings suggest that additional mechanisms beyond reduced food intake may contribute to the greater weight loss observed in aged mice. Together, our findings highlight age as a key determinant of the systemic response to GDF15.