Cambridge collaborators unravel the neuronal circuitry keeping metabolism and fat storage in check

8th April 2009

Scientists at the Babraham Institute, the MRC Laboratory of Molecular Biology and the University of Cambridge have unravelled novel aspects of the biochemical signalling pathways that enable the tiny roundworm, C. elegans, to modify its metabolism in response to food using a neurochemical signalling system that has parallels in mammals.

To survive and reproduce, animals must be able to modify their food-seeking behaviour and metabolism in response to food availability in their environment, migrating to more favourable locations where food is more plentiful.  Although C. elegans is some evolutionary distance from humans, numerous biological processes have been conserved in animals and this tiny transparent worm is proving a usefultool to study the genes regulating fat storage and energy; genes regulating fat metabolism in C. elegans have mammalian counterparts also involved with fat storage. Further C. elegans’ simpler nervous system of only 302 neurons facilitates analysis at the molecular and neural levels compared to higher animals. Special sensory neurons detect food availability and if food is absent or very poor the worm relocates to a more fruitful environment.

The findings, reported today in the journal Cell Metabolism, provide new insights into the ways animals modify their foraging behaviour in response to food availability, thereby enabling them to regulate their energy expenditure, appetite, fat storage and thus survive when food is scarce. The authors reveal that disrupting neuropeptide signalling - knocking out a gene called flp-18 that encodes critical neurochemical transmitters - results in altered metabolism, excess fat accumulation, and defects in the animal’s sense of smell and food seeking behaviour. Further, they identify specific cell membrane receptors, NPR-4 and NPR-5, which communicate signals between the nervous system and various target tissues, including the intestine, to keep energy expenditure in check with food availability.

Cells have to be ready to respond to signals in their environment, such as hormones or signals of nutrient availability. G protein-coupled receptors (GPCRs) are a large family of proteins that play a critical role in relaying signals from other cells and the environment; they sense molecules outside the cell, triggering biochemical cascades inside the cell to activate a cellular response, for example a change in metabolism in response to food. In animals, the NPY/RFamide GPCR family and their associated chemical signalling partners (ligands) operate together to maintain metabolic rate, regulate energy expenditure and fat storage. One such ligand, NPY, promotes appetite and another, PYY, which is released from the gut after eating provides feedback to limit further food intake.

C. elegans has 12 members of the NPY/RFamide receptor family in its genome and at least 23 RFamide genes, called flp genes. In this paper the Cambridge collaborators examine the interplay between specific receptors and flp genes to ascertain how food-seeking behaviour is co-ordinated with metabolism. Worms with mutations in the flp-18 gene have problems in sensing food and foraging behaviour, lay down increased amounts of intestinal fat and have slower metabolism. The authors also identify two receptors, NPR-4 and NPR-5, which are activated by the peptide products of the gene flp-18. They reveal that signalling via NPR-4 enables information to be relayed between the nervous system and the intestine.

Peptides encoded by flp-18 therefore appear to have a central role regulating food-seeking behaviour, fat accumulation and metabolism in response to food related signals in order to maintain a balance between food intake and energy expenditure. Owing to the evolutionary conservation of these mechanisms, studying the genetic and biochemical mechanisms behind food seeking behaviour in one of the simplest multi-cellular animals may also provide valuable insights into this process in humans.  This research was supported with funding from the Biotechnology and Biological Sciences Research Council and Medical Research Council.

Publication details:

Cohen M, Reale V, Olofsson B, Knights A, Evans PD, de Bono M (2009)
Coordinated regulation of foraging and metabolism in C. elegans by RFamide neuropeptide signalling.
Cell Metabolism 9 375-385
http://dx.doi.org/10.1016/j.cmet.2009.02.003

Contact details:

Dr Claire Cockcroft
Head. External Relations
Email: claire.cockcroft@babraham.ac.uk
Tel: +44 (0)1223 496260
Mobile: +44 (0)7786 335978

Dr Peter Evans
Tel: +44 (0)1223 496406
Email: peter.evans@babraham.ac.uk

The Babraham Institute
Babraham Research Campus
Cambridge CB22 3AT
United Kingdom

Notes to Editors:

The Babraham Institute is a charitable organisation devoted to biomedical research and is an institute of the Biotechnology and Biological Sciences Research Council (BBSRC). The Institute’s research is focused on understanding the biological events that underlie the normal functions of cells and on how their failure or abnormality may lead to disease. As such, Institute scientists are striving to find cures for conditions where there is currently no treatment or where the existing treatment is not fully effective or causes serious side effects. The latest technologies are being used to study the basis of conditions such as neurodegenerative disorders, birth defects, cancer and diseases of the immune and cardiovascular systems. With a strategic focus on ‘healthy ageing’, novel approaches for tackling chronic diseases and public health concerns like obesity are being discovered. The Institute’s innovative research is commercialised through Babraham Bioscience Technologies (BBT) Ltd, which also manages Babraham’s vibrant Bioincubator on the Babraham Research Campus, six miles south-east of Cambridge.  Website: www.babraham.co.uk