The ETS-5 transcription factor regulates activity states in Caenorhabditis elegans by controlling satiety

Abstract

Animal behavior is shaped through interplay among genes, the environment, and previous experience. As in mammals, satiety signals induce quiescence in Caenorhabditis elegans. Here we report that the C. elegans transcription factor ETS-5, an ortholog of mammalian FEV/Pet1, controls satiety-induced quiescence. Nutritional status has a major influence on C. elegans behavior. When foraging, food availability controls behavioral state switching between active (roaming) and sedentary (dwelling) states; however, when provided with high-quality food, C. elegans become sated and enter quiescence. We show that ETS-5 acts to promote roaming and inhibit quiescence by setting the internal "satiety quotient" through fat regulation. Acting from the ASG and BAG sensory neurons, we show that ETS-5 functions in a complex network with serotonergic and neuropeptide signaling pathways to control food-regulated behavioral state switching. Taken together, our results identify a neuronal mechanism for controlling intestinal fat stores and organismal behavioral states in C. elegans, and establish a paradigm for the elucidation of obesity-relevant mechanisms.ETS transcription factor | neuronal signaling | satiety | fat levels | quiescence A nimal behavior is strongly influenced by the availability of food. In invertebrates and vertebrates, appetite, locomotor activity, and sleep rhythms are all driven by nutritional state (1-7). When malnourished, animals seek out a new food source by actively exploring their environment (roaming), whereas animals that are well fed tend to explore less (dwelling) and when fully sated enter a quiescent or sleep-like state (1-3, 8, 9). Transitions between these behavioral states can be regulated by sensory perception of external stimuli and through gut signals or other internal cues that are generated according to food quality (3,4,6).Initial evidence for neuronal regulation of feeding behavior was shown in mammals using hypothalamic lesions (10). Sectioning of specific regions within the rat hypothalamus evoked opposing behaviors. Removal of one section caused overeating and obesity, whereas removal of an adjacent section resulted in starvation owing to reduced eating (10). Subsequent studies showed that the pro-opiomelanocortin-expressing neurons in the hypothalamus function to suppress feeding, whereas a hypothalamic region that contains neuropeptide Y/agouti-related protein-expressing neurons promotes feeding (11). These adjacent brain regions integrate signals received from the gut that report satiety (12). The nutritive content of food itself also serves as a potent regulator of behavior. In mammals, a diet loaded with fats and sugars stimulates overfeeding and leads to obesity (13). In addition, rats can learn to select a source of food based exclusively on its nutritional value in the absence of external cues (14).In Caenorhabditis elegans, as in mammals, nutritive value is a behavioral stimulus (1, 4). Nematodes exhibit different behaviors when cultured on low-quality food compared to high-quality...

Transcriptional control of satiety in Caenorhabditis elegans

“…We hypothesized that ets-5 mutants likely exhibit increased quiescence because they are fully sated. Consistent with this, when we decreased fat levels in the intestine of the ets-5 mutant, by malnourishing worms or by reducing the expression of POD-2, an acetyl carboxylase, which is crucial for fatty acid synthesis in the intestine, animals explored more 4 . Thus, decreasing intestinal energy stores overrides the ets-5 mutant quiescence phenotype.…”

“…As such, transcriptional regulation potentiates longer-lasting responses to environmental cues that complement fast-acting synaptic responses 1 . We recently identified a member of the E twenty-six transcription factor family in C. elegans , named ETS-5, which acts in a specific set of neurons to modulate fat storage in the intestine 4 . Here we further expand and explain our findings, and discuss their significance in relation to the most recent work in this field.…”

“…We used a mutant for the 5HT receptor MOD-1, which explores more than wild type animals, 7 to study the relationship between 5HT signaling and ETS-5 function. We found that when both 5HT signaling and ETS-5 are absent, these mutants exhibit normal levels of quiescence, yet still have reduced exploration 4 . This suggests that ETS-5 acts genetically downstream of 5HT signaling in terms of promoting exploratory behavior, but 5HT is genetically upstream of ETS-5 in terms of promoting quiescence, thus highlighting the exquisite complexity of the neural networks that govern behavioral-state switches.…”

“…Our recent study found that ets-5 mutant animals exhibit increased quiescence behavior and store more intestinal fat than wild type animals 4 . We hypothesized that ets-5 mutants likely exhibit increased quiescence because they are fully sated.…”

“…Indeed, we found that neuropeptide secretion from the ASG/BAG neurons is important for them to fulfil this function. We showed that knocking down UNC-31, a protein required for neuropeptide secretion, 19 specifically in the ASG/BAG neurons of wild type animals significantly decreased exploratory behavior 4 . Which neuropeptides are being regulated by ETS-5 still remains an open question.…”