Brain innate immunity regulates hypothalamic arcuate neuronal activity and feeding behavior

Area of Science:

• Neuroscience
• Endocrinology
• Immunology

Background:

• Hypothalamic inflammation, particularly involving microglia in the arcuate nucleus (ARC), is implicated in obesity and metabolic dysfunction.
• The precise role of activated microglia in modulating ARC neuronal activity and subsequent feeding behavior remains unclear.

Purpose of the Study:

• To investigate whether activated microglia influence ARC neuronal activity and affect basal and hormone-induced food intake.
• To elucidate the role of toll-like receptor-4 (TLR4) signaling in microglia-mediated regulation of feeding behavior.

Main Methods:

• Utilized lipopolysaccharide (LPS) as a toll-like receptor-4 (TLR4) agonist to activate microglia in the ARC.
• Recorded neuronal firing activity of orexigenic agouti gene-related protein/neuropeptide Y and anorexigenic proopiomelanocortin neurons.
• Investigated the effects of microglia inhibition and TLR4 receptor blockade on neuronal activity and feeding behavior.
• Assessed the impact of hypothalamic microglia modulation on basal and ghrelin-induced food intake.

Main Results:

• Lipopolysaccharide (LPS) inhibited orexigenic agouti gene-related protein/neuropeptide Y neuron firing while activating anorexigenic proopiomelanocortin neurons.
• These LPS effects on agouti gene-related protein/neuropeptide Y neurons were blocked by inhibiting microglia or TLR4 receptors.
• Inhibition of hypothalamic microglia altered basal food intake and abolished central orexigenic responses to ghrelin.

Conclusions:

• A TLR4-mediated microglia signaling pathway plays a significant role in regulating ARC neuronal activity.
• This pathway is critical for controlling feeding behavior, including responses to hormones like ghrelin.
• Findings highlight hypothalamic microglia as a key player in metabolic regulation and suggest therapeutic potential.