Metabolism: Muscle signals to the rescue
The skeletal muscle of fruit flies communicates with other organs to prevent the accumulation of too much fat and to protect adults against obesity.
- Department of Medicine, University of Colorado Anschutz Medical Campus, United States
When indulging in a tasty meal, we rarely consider the amount of communication that takes place between various organs in our bodies. A multitude of signals flow between the digestive system and the brain, which regulate our appetite and help the body to metabolize foods by extracting nutrients and converting them into energy. However, much remains unknown about the molecular signaling pathways that regulate this internal conversation.
Fruit flies use many of the same mechanisms as humans to regulate food intake and balance energy levels, and are therefore a popular model for studying metabolism and metabolic diseases (Doane, 1960; Baker and Thummel, 2007; Musselman and Kühnlein, 2018). By manipulating the activity of individual genes in specific tissues, researchers have been able to gain more insight into how organs communicate on a molecular level. For example, it emerged that skeletal muscle – as opposed to cardiac and smooth muscle – is the source of a variety of metabolic signals that induce changes in other tissues, some of which have been found to affect the storage of fat (Benatti and Pedersen, 2014; Fisher and Maratos-Flier, 2015; Eckel, 2019). Now, in eLife, Arpan Ghosh, Norbert Perrimon and colleagues – who are based at Harvard Medical School and the Harvard Chan Bioinformatics Core – report that a signaling molecule released by skeletal muscle can protect flies from becoming obese (Ghosh et al., 2020).
The researchers studied a molecule called Pvf, which is the equivalent of two signaling factors that regulate cell growth and division in humans, called PDGF and VEGF. Fruit flies have multiple versions of the Pvf protein, which Ghosh et al. deactivated in various tissues. The experiments revealed that one of these subtypes, called Pvf1, protects adult flies against obesity by preventing excess fat from accumulating in storage sites (the fly adipose tissue) and in specialized cells called oenocytes. Oenocytes help the body absorb and break down fats to provide additional energy to cells in times of stress (Makki et al., 2014).
Ghosh et al. found that oenocytes contained high numbers of PvR, the receptor for Pvf1. When the receptor in these cells was deactivated, the flies stored more fat, similar to what was observed when the production of Pvf1 was turned off in the skeletal muscle. This suggests that communication between the muscle and oenocytes via Pvf1 and its receptor PvR is required to regulate the fat metabolism in the adult fly.
Further experiments showed that blocking a specific signaling pathway (called PI3K/Akt1/TOR) in oenocytes also led to an accumulation of fats, while reactivating the pathway prevented it. Moreover, when Pvf1 was turned off in the skeletal muscle, the signaling pathway in the oenocytes was also impaired. To better understand the role of this pathway in fat mobilization and synthesis, the researchers measured the rates of fat release from stores and new fat synthesis. Blocking this pathway had no effect on mobilizing fat from fat stores. Instead, fat synthesis increased, although the underlying mechanisms remain unclear.
To find out if this communication pathway is more important at a specific point in a fly’s life, Ghosh et al. turned their attention to young adult flies. During this age, the animals rapidly accumulate fat before achieving the steady, balanced level characteristic of mature adults. Indeed, the production of Pvf1 in the adult muscle peaked around the time when adult fat stores in the adipose tissue reached a steady-state capacity. However, when the flies were genetically modified to produce Pvf1 in the muscle earlier than normal and at higher levels, the young adults failed to store as much fat. This suggests that Pvf1 needs to be produced at a specific time and quantity to help young adult flies accumulate the right amount of fat.
Taken together, these findings show that Pvf1 released from skeletal muscle helps to end the normal increase of fat stores in young adult flies. This slows down the production of new fat, thus preventing obesity in mature adults. These results provide new insights into how internal organs communicate with each other to maintain energy levels. Further studies are needed to better understand how this muscle-derived signaling cascade regulates fat accumulation in vertebrates.
References
-
Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulationNature Reviews Rheumatology 11:86–97.https://doi.org/10.1038/nrrheum.2014.193
-
Myokines in metabolic homeostasis and diabetesDiabetologia 62:1523–1528.https://doi.org/10.1007/s00125-019-4927-9
-
Understanding the physiology of FGF21Annual Review of Physiology 78:223–241.https://doi.org/10.1146/annurev-physiol-021115-105339
-
The development and functions of oenocytesAnnual Review of Entomology 59:405–425.https://doi.org/10.1146/annurev-ento-011613-162056
-
Drosophila as a model to study obesity and metabolic diseaseThe Journal of Experimental Biology 221:jeb163881.https://doi.org/10.1242/jeb.163881
Article and author information
Author details
Publication history
Copyright
© 2020, Diaz and Reis
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,388
- views
-
- 82
- downloads
-
- 0
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Metabolism: Muscle signals to the rescue
eLife 9:e64587.
https://doi.org/10.7554/eLife.64587
Further reading
-
- Genetics and Genomics
- Microbiology and Infectious Disease
Polyamines are biologically ubiquitous cations that bind to nucleic acids, ribosomes, and phospholipids and, thereby, modulate numerous processes, including surface motility in Escherichia coli. We characterized the metabolic pathways that contribute to polyamine-dependent control of surface motility in the commonly used strain W3110 and the transcriptome of a mutant lacking a putrescine synthetic pathway that was required for surface motility. Genetic analysis showed that surface motility required type 1 pili, the simultaneous presence of two independent putrescine anabolic pathways, and modulation by putrescine transport and catabolism. An immunological assay for FimA—the major pili subunit, reverse transcription quantitative PCR of fimA, and transmission electron microscopy confirmed that pili synthesis required putrescine. Comparative RNAseq analysis of a wild type and ΔspeB mutant which exhibits impaired pili synthesis showed that the latter had fewer transcripts for pili structural genes and for fimB which codes for the phase variation recombinase that orients the fim operon promoter in the ON phase, although loss of speB did not affect the promoter orientation. Results from the RNAseq analysis also suggested (a) changes in transcripts for several transcription factor genes that affect fim operon expression, (b) compensatory mechanisms for low putrescine which implies a putrescine homeostatic network, and (c) decreased transcripts of genes for oxidative energy metabolism and iron transport which a previous genetic analysis suggests may be sufficient to account for the pili defect in putrescine synthesis mutants. We conclude that pili synthesis requires putrescine and putrescine concentration is controlled by a complex homeostatic network that includes the genes of oxidative energy metabolism.
-
- Genetics and Genomics
Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in Caenorhabditis elegans. Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various ubr-1 mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of ubr-1 is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca2+ activity is diminished in ubr-1. Additionally, enhancing glutamate uptake in ubr-1 mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in C. elegans.
