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.
Highlights
Serotonin, a central neuromodulator with ancient ties to feeding and metabolism, is a major driver of body fat loss
Our previous work describing the 5-HTergic neural circuit revealed that rather than 5-HT itself, an unknown neuroendocrine factor is released from the nervous system and relayed to metabolic tissues to stimulate body fat loss[1]
Here, we present the identification of a secreted neuroendocrine peptide called FLP-7 and its cognate in vivo GPCR neuropeptide receptor-22 (NPR-22), the ancestral orthologues of the tachykinin/neurokinin signalling system, as the neuroendocrine signalling axis that connects the 5-HT circuit from the nervous system, to its metabolic actions in the intestine
Summary
A central neuromodulator with ancient ties to feeding and metabolism, is a major driver of body fat loss. 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 acts via the NPR-22/Tachykinin[2] receptor in the intestine and drives fat loss via the adipocyte triglyceride lipase ATGL-1 This ligand-receptor pair does not alter other serotonin-dependent behaviours including food intake. The central nervous system plays a critical role in regulating energy balance and body fat stores, distinct from its effects on feeding behaviour. Loss of the TPH-1 enzyme leads to undetectable levels of neuronal 5-HT and a significant increase in body fat reserves accompanied by decreased energy expenditure. The primary components of the 5-HT pathway: the biosynthetic enzyme and the receptor, reside in the nervous system, and the collective evidence indicates that
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