Neuronal SKN-1B Modulates Nutritional Signalling Pathways and Mitochondrial Networks to Control Satiety

Abstract

The feeling of hunger or satiety results from integration of the sensory nervous system with other physiological and metabolic cues. This regulates food intake, maintains homeostasis and prevents disease. In C. elegans, chemosensory neurons sense food and relay information to the rest of the animal via hormones to control food-related behaviour and physiology. Here we identify a new component of this system, SKN-1B which acts as a central food-responsive node, ultimately controlling satiety and metabolic homeostasis. SKN-1B, an ortholog of mammalian NF-E2 related transcription factors (Nrfs), has previously been implicated with metabolism and respiration, because can mediate the increased lifespan incurred by dietary restriction. We show that actually SKN-1B is not essential for dietary restriction longevity and instead, controls a variety of food-related behaviours. It acts in two hypothalamus-like ASI neurons to sense food, communicate nutritional status to the organism, and control satiety and exploratory behaviours. This is achieved by SKN-1B modulating endocrine signalling pathways (IIS and TGF-β), and by promoting a robust mitochondrial network. Our data suggest a food-sensing and satiety role for mammalian Nrf proteins.

Olfactory chemosensation extends lifespan through TGF-β signaling and UPR activation

“…Expression levels of daf-7 have been previously linked to activation of the guanylate cyclase DAF-11 in ASI neurons during starvation 24 . We therefore asked whether DAF-11 is also required for UPR ER activation upon 1-undecene exposure, and observed that DAF-11 was indeed necessary for transcriptional upregulation of xbp-1s and the XBP-1 target gene Y41C4A.11 (Fig.…”

The regulation of animal behavior by cellular stress responses

“…SKN-1B, in contrast to the A and C isoforms is expressed specifically in the chemosensory ASI neurons and lacks functionally important features of other SKN-1 isoforms including the crucial DIDLID motif [ 67 ]. This isoform has also been implicated in the remodelling of mitochondrial networks in another tissue, the muscle, suggesting that cell non-autonomous signaling downstream of SKN-1B has profound physiological effects in a distant tissue [ 74 ]. Thus, SKN-1 responds to a broad range of stresses in an isoform specific manner.…”

“…Indeed, foraging behaviour is impaired in animals with null mutations in skn-1 , with skn-1 animals remaining on limited food when wild-type animals would instead choose to forage for more abundant food [ 75 ]. Recent work directly attributes this reduction in exploratory behaviour to SKN-1B, demonstrating that a null allele specific for that isoform recapitulates this foraging defect and that transgenic rescue of skn-1b rescues foraging behaviours [ 74 ].…”

“…When fasted C. elegans are re-fed, they enter a state termed satiety induced quiescence, in which they cease pharyngeal pumping and movement. Animals lacking skn-1b quiesce for longer than wildtype under these conditions, suggesting that this behaviour is also modulated by skn-1 [ 74 ]. Ablation of the ASI neurons has the opposite effect on satiety quiescence, suggesting that this is not a consequence of cell death or inactivity of the ASI neurons [ 76 ].…”

“…SKN-1B requires DAF-7 in order to promote satiety induced quiescence, and expression of daf-7 is increased in skn-1b null animals. SKN-1B also regulates the secretion of insulin like peptides in order to regulate the amount of food that animals consume, and interacts with the regulation of quiescence resulting from reduced insulin signaling [ 74 ]. Therefore, neuropeptide signaling downstream of SKN-1B regulates multiple aspects of the organismal behavioural response to food in parallel to major physiological changes including mitochondrial remodelling and enabling dietary restriction induced longevity.…”