Beyond cellular distress: reframing GDF15 as a lipid-sensitive metabolic signal

Area of Science:

• Metabolic Physiology
• Endocrinology
• Lipid Metabolism

Background:

• Growth Differentiation Factor 15 (GDF15) is traditionally viewed as a hormone signaling somatic distress.
• However, its elevation in common metabolic states, like obesity and type 2 diabetes, suggests a more specific role.
• Emerging evidence links GDF15 levels to fatty acid availability exceeding cellular capacities.

Purpose of the Study:

• To synthesize evidence repositioning GDF15 as an endocrine sensor of lipid load.
• To explore GDF15's role in metabolic adaptation to lipid overload.
• To understand GDF15's function beyond a general stress response.

Main Methods:

• Review of emerging evidence on GDF15 regulation and function.
• Analysis of GDF15's response to various lipid-related conditions (dietary, fasting, overnutrition, ketogenic diets, mitochondrial dysfunction).
• Examination of GDF15 signaling pathways, including its receptor GFRAL.

Main Results:

• Free fatty acids induce GDF15 expression in multiple tissues (kidney, liver, intestine, adipose tissue macrophages) via lipid-sensitive transcriptional pathways.
• Elevated GDF15 activates hindbrain GFRAL signaling, increasing sympathetic outflow and promoting whole-body fatty acid oxidation.
• GDF15 facilitates lipid redistribution and enhances metabolic flexibility, independent of reduced food intake.

Conclusions:

• GDF15 functions as a lipid-responsive hormonal signal, crucial for adapting to lipid overload.
• It forms a feedback system matching fatty acid oxidation with supply, similar to insulin's role in glucose homeostasis.
• Targeting the GDF15 pathway offers potential therapeutic strategies for metabolic disorders like obesity, type 2 diabetes, and MASLD.