Study: A homeostatic gut-to-brain insulin antagonist restrains neuronally stimulated fat loss . Image Credit: Heiti Paves / Shutterstock.com This study highlights a novel mechanism of gut-to-brain communication crucial for lipid metabolism.
In a recent study published in Nature Communications , researchers identify an endogenous insulin antagonist that modulates fat loss in the roundworm Caenorhabditis elegans . How is information transmitted between the nervous system and intestines? The central nervous system (CNS) plays a significant role in systemic lipid homeostasis. Additionally, endocrine hormones signal from peripheral organs to relay fasted and fed state information throughout the body.
The intestines transmit internal state information to the brain and other organs through gut hormones. In the roundworm C. elegans , the utilization of lipids, which are primarily stored and metabolized in the intestine, is determined mainly by sensory neurons and their circuits.
Previously, the current study's researchers identified specific activities by sensory neurons and their role in lipid storage. Whereas URX and BAG neurons can detect and respond to oxygen levels in their surrounding environment, ADL and ADF neurons sense population density and bacterial food, respectively. These researchers also identified FMRFamide-like neuropeptide 7 (FLP-7), a brain-to-gut neuroendocrine peptide involved in relaying sensory information from the nervous system to the intestine.
The secretion of FLP-7 is mediated by both URX and ADL neurons, which is subsequently detected by the neuropeptide receptor 22 (NPR-22). Thus, the FLP-7/NPR-22 axis represents a common brain-to-gut pathway for the sensory nervous system relaying information to the intestine. However, the mechanisms by which peripheral organs relay information to the nervous system in C.
elegans remain unclear, despite evidence suggesting the existence of these signals. Study findings The present study investigates the molecular features underlying gut-to-brain information relay in C. elegans .
An intestine-specific ribonucleic acid interference (RNAi) screen of genes encoding small peptides was performed to identify changes in FLP-7 secretion from ASI neurons (FLP-7 ASI ) in C. elegans , in which insulin-like peptide 7 ( ins-7 ) was identified as the most potent hit. In fact, FLP-7 ASI secretion increased nearly two-fold in the absence of ins-7 .
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Additionally, ins-7 null mutants with increased FLP-7 ASI secretion exhibited significantly reduced intestinal fat stores, which was dependent on the flp-7 gene. Selective inactivation of flp-7 in ASI neurons revealed that the fat phenotype in ins-7 mutants required flp-7 in ASI neurons. The reduction in fat stores in ins-7 nulls was also dependent upon the induction of adipose triglyceride lipase 1 ( atgl-1 ) gene in the presence of flp-7.
The researchers also investigated the relationship between ins-7 and daf-2 , the only insulin receptor in C. elegans . To this end, daf-2 mutants reduced FLP-7 ASI secretion, unlike ins-7 mutants.
ASI neuron-specific daf-2 inhibition phenocopied the global daf-2 mutation, whereas ASI-specific daf-2 rescue restored the secretion of FLP-7 to wild-type levels. The localization of DAF-16 in ASI neurons was determined by examining its cytoplasmic-to-nuclear (C:N) ratio, which is a sensitive and accurate hallmark of DAF-2 function. In well-fed wild-type animals, DAF-16 was present in the cytoplasm with a C:N ratio of 1.
2; however, in daf-2 mutants, DAF-16 was translocated to the nucleus with a C:N ratio of 0.5. In ins-7 mutants and ins-7 -overexpressed worms, the C:N ratio was similar to that of wild-type animals.
These effects were subsequently assessed after a three-hour fasting state, which depletes about 80% of intestinal fat stores. In the fasted state, DAF-16 localization did not shift between cytoplasm and nucleus in wild-type animals, nor ins-7 or daf-2 mutants. Comparatively, in worms with ins-7 overexpression, DAF-16 translocated to the nucleus with a C:N ratio of 0.
8. In the fasted state, DAF-2 and INS-7 colocalized on the ASI neuronal surface in wild-type worms, thus indicating that INS-7 may differentially regulate FLP-7 ASI in fasted and fed states. FLP-7 secretion dynamics were subsequently determined in the absence and presence of ins-7 .
In food-deprived wild-type animals, increased FLP-7 secretion was not evident until three hours. Feeding after three hours restored FLP-7 secretion to baseline levels. This feeding state-dependent FLP-7 regulation was abrogated in ins-7 null mutants, as FLP-7 secretion was chronically high and independent of fed or fasted states.
The dynamics of INS-7 secretion in food-deprived wild-type animals were also assessed. To this end, an increase in INS-7 secretion was observed within thirty minutes of food deprivation and restored to baseline levels upon re-feeding. Conclusions INS-7 is secreted from specialized enteroendocrine INT1 cells of C.
elegans and functions as an antagonist of the DAF-2 receptor in ASI neurons to inhibit FLP-7 secretion. FLP-7 ASI release promotes fat loss; therefore, the gut-to-brain peptide INS-7 limits this signal without sensing food in the intestine. The current study reveals a mechanism of gut-to-brain homeostatic communication in which lipid metabolism balances internal metabolic states and external sensory cues.
Liu, C. C., Khan, A.
, Seban, N., et al . (2024).
A homeostatic gut-to-brain insulin antagonist restrains neuronally stimulated fat loss. Nature Communications . doi:10.
1038/s41467-024-51077-3.
