GDF15 links adipose tissue lipolysis with anxiety.

Summary

Adipose β-adrenergic stimulation (adrenaline/β3 agonist) and acute stress induce GDF15 secretion from white adipose tissue via lipolysis and M2-like macrophage activation. Anxiety-like behavior elicited by stress is abolished in GFRAL-deficient mice, establishing a peripheral endocrine GDF15→GFRAL axis linking metabolism to behavior.

Key Findings

• Adrenaline, β3-agonist CL316,243, and acute restraint stress induce GDF15 secretion from white adipose tissue.
• Lipolysis-driven free fatty acids activate M2-like macrophages to drive GDF15 increases.
• Anxiety-like behavior elicited by stress requires GFRAL; it is eliminated in GFRAL-deficient mice.

Clinical Implications

Targeting GDF15–GFRAL signaling could mitigate acute anxiety without central β-blockade; conversely, therapeutics elevating GDF15 may have neuropsychiatric effects requiring monitoring.

Limitations

• Predominantly murine data; translational generalizability to humans remains to be shown
• Temporal resolution of cellular intermediates in adipose niche could be expanded

Future Directions

Define human relevance in stress paradigms, assess pharmacologic GFRAL antagonism for acute anxiety, and map adipose immune–neural interfaces across metabolic states.