When the supply of environmental nutrients is limited, multicellular animals can make both physiological and behavioral changes so as to cope with nutrient starvation. Although physiological and behavioral effects of starvation are well known, the mechanisms by which animals sense starvation systemically remain elusive. Furthermore, what constituent of food is sensed and how it modulates starvation response is still poorly understood. In this study, we use a starvation-hypersensitive mutant to identify molecules and mechanisms that modulate starvation signaling. We found that specific amino acids could suppress the starvation-induced death of gpb-2 mutants, and that MGL-1 and MGL-2, Caenorhabditis elegans homologs of metabotropic glutamate receptors, were involved. MGL-1 and MGL-2 acted in AIY and AIB neurons, respectively. Treatment with leucine suppressed starvation-induced stress resistance and life span extension in wild-type worms, and mutation of mgl-1 and mgl-2 abolished these effects of leucine. Taken together, our results suggest that metabotropic glutamate receptor homologs in AIY and AIB neuron may modulate a systemic starvation response, and that C. elegans senses specific amino acids as an anti-hunger signal.Supplemental material is available at http://www.genesdev.org.Received July 31, 2008; revised version accepted November 14, 2008. During nutritional deprivation, individual cells can respond to starvation by modulating intracellular signaling, which in turn induces a starvation response and thereby enhances their survival (Levine and Yuan 2005;Lum et al. 2005;Levine and Kroemer 2008). An important starvation response of individual cells is a change of metabolism (inhibiting anabolic pathways and activating catabolic pathways), so as to generate metabolic substrates to maintain basal cellular activities (Lum et al. 2005). In multicellular organisms, however, the situation is complicated by the need to induce behavioral changes in addition to physiological changes, and more importantly by the danger that uncoordinated starvation responses in individual cells could be harmful to the organism. In Caenorhabditis elegans, for example, we reported previously that excessive autophagy in pharyngeal muscle causes its malfunction, which eventually prevents the recovery of worms from starvation (Kang et al. 2007). Thus, it is important that multicellular organisms ensure their starvation response is coordinated between individual cells, and therefore it is plausible to assume that there are mechanisms by which animals sense starvation systemically.Since animals cannot synthesize several amino acids, so-called ''essential acids,'' they must ingest these amino acids from external food sources to maintain homeostasis (Gietzen and Rogers 2006). C. elegans also requires certain amino acids in the diet (Szewczyk et al. 2003). This fact leads to the intriguing possibility that amino acids act as a food or anti-hunger signal. Indeed, treatment with amino acids can inhibit starvation-induced autophagy in culture...