The serotonergic feeding-regulatory circuit: learning from worms

Serotonin has emerged as a key neurotransmitter that regulates feeding behaviour. Targeting the serotonergic circuitry has therapeutic potential for human obesity, but the key molecules that regulate this circuitry are largely unknown. In Caenorhabditis elegans, it has been shown that serotonin enhances feeding behaviour, and that genetic ablation of tryptophan hydroxylase (tph-1; expressed in certain types of neuron and required for serotonin synthesis) reduces feeding. Cunningham et al. dissected this feeding circuit in more detail to identify additional, evolutionarily conserved components that control feeding behaviour. They show that deletion of tph-1 in chemosensory ADF neurons, but not in NSM pharyngeal neurons, reduces feeding behaviour. The circuit was found to require SER-5, a serotonin receptor, and hlh34, the worm homologue of human SIM1, which encodes a transcription factor expressed in the human paraventricular nucleus (a brain region crucial for maintaining energy homeostasis). Serotonin produced by ADF neurons was found to increase feeding behaviour by inhibiting the activity of AMP-activated kinase (AMPK), another conserved regulator of energy balance, in hlh34-expressing neurons. AMPK inhibition led to increased glutamate neurotransmitter release by hlh34-expressing neurons, stimulating regulation by glutamate-responsive pharyngeal neurons. Finally, the authors demonstrate using rat hippocampal neurons that at least some aspects of this feeding-regulatory circuit also operate in mammals.