In the Belly of the Beast

A new study recently published in BMC Genomics suggests a single gene, F10, is the potential modulator for the system wide metabolic regulation that allows Burmese pythons to increase the mass of key organs by an astonishing 40-100% in the days after feeding.

Serpents are perhaps one of the most unique reptiles on the planet, both in form and function. They have adapted to movement without legs, hunting mechanisms range from venomous fangs to suffocation, and a metabolism that can quickly adapt between feast and prolonged famine.

Unsurprisingly, the metabolic changes that take place within serpentine metabolism have long fascinated scientists, who work towards understanding how the snake body could undergo such rapid changes without harming the animal.

The Burmese python in particular is an excellent model for physiological studies since it is such a large snake (in the wild averaging just over twelve feet) with a sturdy build. Full grown adults can go months between feeding, but then consume an entire goat or pig.

Some of the most notable changes that take place within the Burmese python before and after they feed occur within their organ systems, with major organs such as the heart, liver and kidneys increasing in mass by 40-100% two days after consuming a meal. On a cellular level, their metabolism skyrockets to a 44-fold increase, with more then 100-fold increase in plasma triglyceride content in their blood stream.

Ten to fourteen days after the python has consumed a meal, these same organs undergo atrophy and shrink back down to pre-meal sizes and metabolism.

From a genomic perspective, transcriptional responses (as expected) are both rapid and massive in regards to both the magnitude of expression changes and in the number of genes with significant differential expression. Previous studies have indicated that these changes are likely a result of a conserved response to core signaling molecules, which in turn activate diverse, tissue-specific signaling cascades. However, the identity of these signaling molecules has not yet been discovered due to the sheer scale and abbreviated time frame within which these changes take place in the genome.

Audra Andrew and Blair Perry at the University of Texas, Arlington and colleagues have recently published a study in BMC Genomics in which they analyzed the genomic changes that take place within the heart, liver, kidneys, and small intestine of the Burmese python before, during, and just after feeding.

Of particular interest was the LXR/RXR activation pathway, PI3K/AKT, and mTOR signaling involved in upregulating the growth processes of organs, and the NRF2-mediated oxidative stress response pathways with regards to the stress response.

This study was conducted by taking groups of Burmese pythons, fasting them for 30 days, and then feeding them a meal equal to 25% of their body mass. Tissue sampling time points were 30 days post fasting, one day after being fed, and 4 days after being fed, and collected from the heart, liver, small intestine and kidney. The tissue samples were then run though NEB Next RNAseq to generate RNAseq libraries for analysis.

To determine pathway activation and regulatory molecule predictions, the authors annotated the full Burmese python transcription set with the orthologous human gene Ensembl identifiers. The program STEM was used to identify and visualize significant expression profiles for all genes within the samples.

Once data on the full set of python genes was collected, the specific genetic effects over the time period were assessed, and changes in upregulation and regression were noted.

Figure 2A from Andrew et al. 2017. Summary of significantly differentially expressed genes for all four organs identified via regression analysis. This Venn diagram depicts the numbers of genes significantly differentially expressed across time points. Darker colors indicate a large number of genes and lighter colors indicate a smaller number of genes.

For every organ studied, the majority of differentially expressed genes showed immediate up or down regulation within 24 hours post feeding. Each of the four organs examined experienced regression towards fasting levels of expression by four days post fasting to widely different extents, indicating that growth changes are unique between organ systems. Of all genes in the genome, only a single gene was identified as significant in all four organs across all time points: coagulation factor X (F10).

After mapping the python genes to human orthologs, Andrew and colleagues were able to associate over 70% of human genes within the mTOR and NRF2 stress response pathway.  Both of these biological pathways appear to be involved in every organ system response to feeding, suggesting human tissue is likely to have developed in the same manner. Notably, insulin signaling represents a key-regulation factor of the mTOR pathway, and the activation of NRF2 may play additional roles in growth response, as its blood plasma contains factors that have been shown in vitro to cause resistance to apoptosis in mammalian cells.

While this scale of hypertrophy, hyperplasia and atrophy are impressive in snakes, it is not a unique phenomenon in the animal kingdom, as other classes of animals – notably fish and amphibians – as well as plants express varying levels of organ and tissue growth and regeneration. However, the use of mTOR and NRF2-mediated signaling is unique to the Burmese python in both phenotype and genotype expression patterns, particularly the use of multiple coordinated growth pathways in multiple tissue types, suggesting a possible future mechanism to facilitate future human growth and organ repair.

BMC-series Editor Cecilia Devoto, and python.



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