Lipids Engage a Kidney-Brain GDF15 Axis to Suppress Food Intake

Area of Science:

• Metabolic signaling
• Gut-brain axis
• Hormonal regulation

Background:

• Lipid sensing in the upper small intestine influences systemic metabolism and feeding behavior.
• Growth differentiation factor 15 (GDF15) is implicated in appetite regulation and metabolic homeostasis.
• The role of GDF15 and its receptors in response to intestinal lipid loads requires further elucidation.

Purpose of the Study:

• To investigate the impact of upper small intestine lipid infusion on GDF15 levels and food intake in rats fed different diets.
• To determine the involvement of kidney-derived GDF15 and the GDNF family receptor α-like (Gfral) in the area postrema in mediating these responses.

Main Methods:

• Rats were fed either a chow or high-fat diet and received upper small intestine lipid infusions.
• Kidney Gdf15 or area postrema Gfral were knocked down using specific genetic techniques.
• Plasma and tissue GDF15 levels, along with food intake, were measured.

Main Results:

• Lipid infusion increased kidney, hepatic, and plasma GDF15 in chow-fed rats but not high-fat-fed rats.
• Food intake was reduced by lipid infusion in chow-fed rats, an effect blunted in high-fat-fed rats.
• Kidney Gdf15 knockdown abolished the lipid-induced increase in plasma GDF15 and the reduction in feeding.
• Area postrema Gfral knockdown negated the anorectic effect of lipid infusion.

Conclusions:

• Kidney GDF15 plays a crucial role in mediating the systemic GDF15 elevation and appetite suppression following upper small intestine lipid exposure.
• The area postrema GFRAL pathway is essential for sensing intestinal lipid signals to control feeding behavior.
• Diet composition significantly modulates the physiological responses to upper small intestine lipid loads.