Communication between the sensory nervous system and remote metabolic tissues is emerging as an important controller of animals' fat stores. Despite its significance, there is a major gap in our mechanistic understanding of how the sensory nervous system regulates fat metabolism in remote tissues, and vice versa. Members of the salt-inducible kinase (SIK) family play central roles in metabolic regulation. As in mice and Drosophila (Wang et al. 2011; Uebi et al. 2012), we found a conserved role for the SIK3 homolog KIN-29 in C. elegans in metabolic regulation. We show that
kin-29(lf) mutants exhibit increased body fat levels as determined by lipid-staining, CARS microscopy, and triglyceride quantification. The increase in body fat of
kin-29(lf) mutants is not accompanied by a change in food intake, but instead these mutants show increased exploratory foraging activity (e.g. food leaving, roaming). Restoring
kin-29 function in
odr-4-expressing chemosensory neurons, but not in the intestine, rescues the increased body fat and exploratory activity of
kin-29 mutants. These observations suggest that the shift in metabolism in
kin-29 mutants may be the result of deficits in sensory perception of food rather than food intake. KIN-29 acts via a conserved MEF2/HDAC pathway to regulate sensory gene expression (van der Linden et al. 2007). We show that
kin-29-mediated control of body fat and exploratory activity requires the function of the
mef-2 transcription factor in
odr-4-expressing neurons. To further determine how KIN-29 function controls body fat and foraging, we profiled the transcriptome from whole animals and
odr-4-expressing neurons of adult wild-type,
kin-29 and
kin-29;
mef-2 mutants using the mRNA polyA-tagging method coupled to RNA-seq. We identified genes up- and downregulated in a
kin-29- and
mef-2-dependent manner. Among these genes,
rbg-3 RabGap encoding the TBC1D5 homolog in C. elegans is increased (3-fold) in amphid neurons in
kin-29 mutants, and these expression changes are dependent on
mef-2. We show that
rbg-3(lf) mutations can suppress the increased body fat, and in part, exploratory foraging of
kin-29, suggesting that
rbg-3 acts downstream of KIN-29 in the regulation of body fat and foraging. We are currently investigating whether KIN-29 via MEF-2 function acts directly on
rbg-3 expression. These results suggest a model in which KIN-29 signaling via MEF-2 employs a RBG-3/Rab-mediated pathway to non-autonomously coordinate fat metabolism.