A tachykinin-like neuroendocrine signalling axis couples central serotonin action and nutrient sensing with peripheral lipid metabolism

Abstract

Serotonin, a central neuromodulator with ancient ties to feeding and metabolism, is a major driver of body fat loss. However, mechanisms by which central serotonin action leads to fat loss remain unknown. Here, we report that the FLP-7 neuropeptide and its cognate receptor, NPR-22, function as the ligand-receptor pair that defines the neuroendocrine axis of serotonergic body fat loss in Caenorhabditis elegans. FLP-7 is secreted as a neuroendocrine peptide in proportion to fluctuations in neural serotonin circuit functions, and its release is regulated from secretory neurons via the nutrient sensor AMPK. FLP-7 acts via the NPR-22/Tachykinin2 receptor in the intestine and drives fat loss via the adipocyte triglyceride lipase ATGL-1. Importantly, this ligand-receptor pair does not alter other serotonin-dependent behaviours including food intake. For global modulators such as serotonin, the use of distinct neuroendocrine peptides for each output may be one means to achieve phenotypic selectivity.

Intestinal peroxisomal fatty acid β-oxidation regulates neural serotonin signaling through a feedback mechanism

“…C. elegans that have been returned to food after a period of fasting transition from a metabolic state that favors energy conservation to an active state of energy utilization. This active metabolic state is driven by elevated serotonin signaling [18,31,32]. If elevated levels of serotonin are maintained by pharmacological or genetic interventions, C. elegans exhibit fat loss [33,34].…”

“…If elevated levels of serotonin are maintained by pharmacological or genetic interventions, C. elegans exhibit fat loss [33,34]. The effects of serotonin on body fat are not simply a byproduct of its effects on food intake as we and other groups have found that molecular and cellular circuits that link serotonin signaling to peripheral energy metabolism are largely independent from those that regulate feeding [18,22,23,31,32,35]. For example, serotonin secreted from the ADF sensory neurons signals through neurally expressed SER-5 serotonergic receptor to modulate feeding.…”

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

“…These behaviours are ideal readouts of the animal's internal nutritional state, as they are modulated by intestinal fat storage and food availability (Ben Arous et al, 2009;Hyun et al, 2016;Shtonda and Avery, 2006). Neuronal signalling pathways, such as serotonin, TGF-b, pigment-dispersing factor and insulin-like signalling, act in concert to simultaneously regulate metabolism, foraging behaviour, reproduction and developmental decisions (Ben Arous et al, 2009;Flavell et al, 2013;Palamiuc et al, 2017;Song and Avery, 2012;You et al, 2008) This integrative neuronal control enables the animal to appropriately modulate behaviour and metabolism in response to diverse and dynamic inputs.…”

Transcriptional control of satiety in Caenorhabditis elegans

“…5HT is synthesized and secreted from a discrete number of neurons in C. elegans , 15 and promotes the breakdown of body fat by inducing ATGL-1 lipase expression in the intestine 12 . 5HT signals to the URX and ASI neurons, which results in secretion of the neuropeptide FLP-7 into the pseudocoelomic fluid 16 . Intestinal cells bind circulating FLP-7 via the NPR-22 receptor, which results in increased ATGL-1 expression 16 .…”

“…5HT signals to the URX and ASI neurons, which results in secretion of the neuropeptide FLP-7 into the pseudocoelomic fluid 16 . Intestinal cells bind circulating FLP-7 via the NPR-22 receptor, which results in increased ATGL-1 expression 16 . Generally, 5HT is a signal of satiety; promoting dwelling behavior and fat breakdown 7,12 .…”