GDF15 links adipose tissue lipolysis with anxiety

Area of Science:

• Metabolic regulation
• Neuroendocrinology
• Behavioral biology

Background:

• Psychological stress alters behavior and metabolism.
• Adrenaline is a key mediator of the stress response.
• Peripheral signals may link metabolic changes to behavioral outcomes like anxiety.

Purpose of the Study:

• To investigate the molecular mechanisms linking stress-induced metabolic changes to anxiety.
• To identify key signaling pathways involved in stress-mediated behavioral responses.

Main Methods:

• Induction of GDF15 secretion in mouse white adipose tissue using adrenaline, a β3 agonist, and restraint stress.
• Genetic manipulation (inhibition of adipose triglyceride lipase, deletion of β-adrenergic receptors) to assess GDF15 regulation.
• Analysis of free fatty acid stimulation of macrophages and GDF15 receptor (GFRAL) knockout models to evaluate anxiety-like behavior.

Main Results:

• Adrenaline, CL316,243, and stress induce growth differentiation factor 15 (GDF15) secretion in white adipose tissue.
• GDF15 induction is dependent on adipose triglyceride lipase and β-adrenergic signaling.
• Increased circulating GDF15 requires lipolysis-driven free fatty acid stimulation of M2-like macrophages.
• Anxiety-like behaviors induced by stress are abolished in GDF15 receptor (GFRAL) knockout mice.

Conclusions:

• Adipose-derived GDF15 acts as a crucial mediator linking metabolic alterations during stress to anxiety-like behavior.
• The GDF15-GFRAL signaling pathway is essential for mediating the behavioral effects of acute stress.
• Targeting GDF15-GFRAL signaling may offer a therapeutic strategy for reducing acute anxiety.