Whole-brain Mapping Reveals Diet-dependent Neuronal Activation and Selective Resistance to Exogenous FGF21

Area of Science:

• Neuroendocrinology
• Metabolic regulation
• Hormonal signaling

Background:

• Fibroblast growth factor 21 (FGF21) is a metabolic hormone produced by the liver.
• FGF21 crosses the blood-brain barrier, interacting with FGFR1c and β-Klotho receptors to influence neuronal activity.
• Previous research identified brain regions expressing FGFR1c and β-Klotho, indicating potential FGF21 targets.

Purpose of the Study:

• To investigate the diet-dependent effects of FGF21 on neuronal activity in the brain.
• To explore how obesity and high-fat diets alter FGF21's central actions.
• To assess FGF21's potential as an anti-obesity therapy by examining its effects on hypothalamic feeding circuits.

Main Methods:

• Utilized mouse models fed either normal chow or a high-fat diet (HFD).
• Measured changes in neuronal activity in response to FGF21 administration under different dietary conditions.
• Analyzed FGF21's impact on specific brain regions, including the hypothalamus and cortex.

Main Results:

• On a normal diet, FGF21 activated metabolic control regions and suppressed cortical areas in mice.
• HFD feeding increased neuronal activity in sensory, memory, and reward regions.
• In HFD-fed mice, FGF21 activated broader brain areas but showed impaired stimulation of key metabolic nuclei, suggesting central FGF21 resistance.

Conclusions:

• FGF21's effects on brain activity are significantly influenced by dietary status.
• Obesity alters the central mechanisms through which FGF21 exerts its effects.
• Selective central FGF21 resistance may occur in the context of obesity, impacting its therapeutic potential.