Oxygen-sensing neurons reciprocally regulate peripheral lipid metabolism via neuropeptide signaling inCaenorhabditis elegans

Abstract

The mechanisms by which the sensory environment instructs metabolic homeostasis remains poorly understood. In this report, we show that oxygen, a potent environmental signal, is an important regulator of whole body lipid metabolism. C. elegans oxygen-sensing neurons reciprocally regulate peripheral lipid metabolism under normoxia in the following way: under high oxygen and food absence, URX sensory neurons are activated, and stimulate fat loss in the intestine, the major metabolic organ for C. elegans. Under lower oxygen conditions or when food is present, the BAG sensory neurons respond by repressing the resting properties of the URX neurons. A genetic screen to identify modulators of this effect led to the identification of a BAG-neuron-specific neuropeptide called FLP-17, whose cognate receptor EGL-6 functions in URX neurons. Thus, BAG sensory neurons counterbalance the metabolic effect of tonically active URX neurons via neuropeptide communication. The combined regulatory actions of these neurons serve to precisely tune the rate and extent of fat loss, to the availability of food and oxygen.

Inferring a spatial code of cell-cell interactions across a whole animal body

“…This is consistent with the role of seam cells during larval development, where they form adherens junctions with sheath cells and hypodermal cells and function as sockets for the phasmid sensilla 55 . Another interesting observation was the high cell-cell interaction score between oxygen sensing neurons and intestinal cells, which is consistent with the extensive communication between these cells to link oxygen availability with nutrient status 56–58 . Thus, the protein-protein interactions prioritized by the GA seem to capture cellular properties that define physical proximity, especially defining functional roles of tissues and organs.…”

“…For example, the complete list grouped neurons and muscles together, while the GA-LR pairs increased the specificity of this association by grouping both excitatory and inhibitory neurons (cholinergic and GABAergic neurons, respectively) directly with all muscles; furthermore, this list grouped all cells composing the pharynx (pharyngeal gland, epithelia, muscle and neurons) together. Another interesting observation was the high CCI score between oxygen sensing neurons and intestinal cells, consistent with the extensive communication between these cells to link oxygen availability with nutrient status (Hussey et al, 2018; Noble et al, 2013; Witham et al, 2016). Thus, the PPIs prioritized by the GA capture cellular properties that define intercellular proximity, especially defining functional roles of tissues and organs.…”

Diet-responsive Transcriptional Regulation of Insulin in a Single Neuron Controls Systemic Metabolism

“…Low O 2 can activate the BAG neurons, which then act to supress the URX neurons through the neuropeptide FLP-17. Under low oxygen conditions, FLP-17 inhibition of URX modulates intestinal lipid breakdown during starvation (Hussey et al, 2018). However, we found that flp-17 mutant animals have wild-type levels of exploration ( Figure 1B).…”

“…These BAG-specific mechanisms likely act in parallel to ensure appropriate metabolic regulation depending on the environmental context of the animal. Since ETS-5 regulates expression of the FLP-17 and FLP-19 neuropeptides (Brandt et al, 2012;Guillermin et al, 2011), O 2 regulates FLP-17 levels (Hussey et al, 2018), and CO 2 -sensing is required for FLP-19 expression (Rojo Romanos et al, 2017), these regulatory modules are likely to be linked in a broader physiological sense -suggesting the idea that activity within the BAG neuron can be precisely tailored according to multiple sensory inputs.…”

“…The BAG neurons are well known for their gas-sensing functions -sensing down-steps in O 2 and acute CO 2 responses (Bretscher et al, 2008;Hallem and Sternberg, 2008;Zimmer et al, 2009). In parallel to these gassensing roles, signals from the BAG neurons control egg-laying, and can modulate the activity of URX neurons to control lipid metabolism (Hussey et al, 2018;Ringstad and Horvitz, 2008). ETS-5 plays a fundamental role in transcriptionally regulating the receptors and neuropeptides involved in these BAG-specific functions (Brandt et al, 2012;Guillermin et al, 2011).…”