Beyond cellular distress: reframing GDF15 as a lipid-sensitive metabolic signal - PubMed
5 hours ago
- #GDF15
- #lipid metabolism
- #metabolic disorders
- GDF15 is traditionally viewed as a hormone signaling somatic distress to the brain, but recent evidence suggests it acts as a lipid-sensitive metabolic signal.
- GDF15 levels increase when fatty acid availability surpasses mitochondrial and endoplasmic reticulum capacity, indicating lipid overload.
- Free fatty acids activate lipid-sensitive pathways that induce GDF15 expression in tissues like kidney, liver, intestine, and adipose tissue macrophages.
- Elevated GDF15 engages GFRAL signaling in the hindbrain to increase sympathetic outflow, promote fatty acid oxidation, and redistribute lipid burden.
- GDF15's metabolic effects occur independently of reduced food intake and involve coordinated actions across liver, adipose tissue, and skeletal muscle.
- Reframing GDF15 as a lipid-responsive hormone provides new insights into metabolic adaptations to lipid overload and potential therapeutic targets for metabolic disorders.
- GDF15 may function as part of a feedback system to match fatty acid oxidation with supply, similar to insulin's role in glucose metabolism.
- Targeting the GDF15 pathway could benefit conditions like obesity, type 2 diabetes, cardiovascular disease, cancer cachexia, and MASLD.