AMP-activated kinase links serotonergic signaling to glutamate release for regulation of feeding behavior in C. elegans.

Serotonergic regulation of feeding behavior has been studied intensively, both for an understanding of the basic neurocircuitry of energy balance in various organisms and as a therapeutic target for human obesity. However, its underlying molecular mechanisms remain poorly understood. Here, we show that neural serotonin signaling in C. elegans modulates feeding behavior through inhibition of AMP-activated kinase (AMPK) in interneurons expressing the C. elegans counterpart of human SIM1, a transcription factor associated with obesity. In turn, glutamatergic signaling links these interneurons to pharyngeal neurons implicated in feeding behavior. We show that AMPK-mediated regulation of glutamatergic release is conserved in rat hippocampal neurons. These findings reveal cellular and molecular mediators of serotonergic signaling.

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