GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans

Summary GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.
Graphical Abstract
Highlights • Dietary changes influencing adipose/gut-derived hormones do not alter GDF15 levels • Chronic high-fat or acute lysine-deficient diet exposure increases GDF15 levels • GDF15 administration triggers conditioned taste aversion in mice • GDF15 is a stress-induced hormone that may mediate an aversive dietary response
Patel et al. show that whereas short-term overfeeding or fasting does not change GDF15 levels substantially, prolonged high-fat feeding and lysine-deficient diets activate the integrated stress response and increase GDF15 levels. GDF15 administration triggers conditioned taste aversion in mice, suggesting that GDF15 might induce an aversive response to nutritional stress.