AMPK mediates energetic stress-induced liver GDF15

Area of Science:

• Metabolic Regulation
• Cellular Stress Response
• Endocrinology

Background:

• Growth differentiating factor-15 (GDF15) suppresses appetite and is a potential therapeutic target for obesity and metabolic disorders.
• GDF15 regulation is linked to cellular stress responses, including endoplasmic reticulum (ER) stress, but the role of AMP-activated protein kinase (AMPK) in vivo remains unclear.

Purpose of the Study:

• To investigate the in vivo relationship between AMPK, ER stress, and GDF15 induction in mouse liver.
• To determine if AMPK activation, under conditions of energetic or ER stress, influences GDF15 expression and secretion, ultimately affecting food intake.

Main Methods:

• Wildtype (WT), AMPK β1 deficient (AMPKβ1-/-), and CHOP-/- mice were treated with three AMPK activators: AICAR, R419, and A769662.
• Post-treatment assessments included liver Gdf15 expression, ER stress markers, AMPK activity, adenine nucleotides, circulating GDF15 levels, and food intake.

Main Results:

• AICAR and R419 induced ER and energetic stress, increasing GDF15 and suppressing food intake.
• Direct AMPK activation (A769662) elevated hepatic and circulating GDF15 and reduced food intake, independent of ER stress.
• The effects of all activators on GDF15 were diminished in AMPKβ1-/- mice, indicating AMPK's crucial role.

Conclusions:

• AMPK activation plays a significant role in mediating GDF15 induction in mouse liver during energetic stress.
• Direct AMPK activation can increase GDF15 and reduce food intake without inducing ER stress.
• These findings highlight AMPK as a key regulator of GDF15 in metabolic homeostasis.