Menu

Close

TORC1 modulation in adipose tissue is required for organismal adaptation to hypoxia in Drosophila.

Byoungchun Lee, Elizabeth C Barretto, Savraj S Grewal

Preprint posted on June 20, 2018 https://www.biorxiv.org/content/early/2018/06/20/350520.1

Hypoxia is deadly to some organisms but well-tolerated by others. New preprint sheds light on how Drosophila larvae are able to survive in low oxygen.

Selected by Sarah Bowling

Categories: developmental biology

Background of the preprint

Development is a time of rapid cellular growth and proliferation. However, variabilities in food, oxygen, temperature and toxin exposure all impact these processes. For organisms such as Drosophila, these factors can vary considerably during larval development. How then do fly larvae achieve robust growth in the face of a fluctuating environment?

In response to nutrient deprivation, environmental sensing is carried out in specific Drosophila tissues such as the fat body, where the nutrient-sensing TOR pathway responds and alters whole body development to promote survival through the modulation of endocrine signalling. However, much less is known about how hypoxia is sensed and tolerated in fly development. Here, the authors aim to answer the question of how fly larvae survive in low oxygen. Since hypoxia contributes to the pathophysiology of various conditions including heart disease, obesity and cancer, gleaning information into how tissues withstand this insult could prove valuable in the treatment of human disease.

Key findings of the preprint

Firstly, the authors demonstrate that TOR signalling is rapidly repressed in response to hypoxia in fly larvae, suggesting that this pathway acts as a sensor of low oxygen levels. These changes in TOR signalling are important for fly larvae to tolerate hypoxia, since preventing TOR repression by overexpression of TOR activator Rheb markedly reduces hypoxia tolerance. Notably, the authors describe marked lethality at the pupal stage in Rheb-overexpressing larvae maintained in hypoxic conditions, a phenotype not observed in wild-type hypoxic or Rheb-overexpressing normoxic larvae.

Secondly, the preprint demonstrates that TOR signalling specifically in the fat body mediates the tolerance to hypoxia. Hyperactivation of TOR signalling in the fat body, but not other larval tissues such as the neurons and intestine, reduces hypoxic larval survival to the pupal stage by around 50%.

Finally, the authors explore the pathways altered downstream of TOR repression which confer hypoxia tolerance. They observe that hypoxia leads to an increase in both lipid droplet size (shown below) and overall lipid storage in a TOR-dependent manner. Blocking lipid droplet remodelling through knockdown of Lsd2, a key protein in lipid droplet formation, triggers high pupal lethality in hypoxic conditions. This final result illustrates that lipid droplet remodelling is vital for the survival of Drosophila larvae in low oxygen.

Lipid droplets in the fat body increase in size in response to hypoxia. Image reproduced with permission from Figure 6 of the preprint.

What I like about this preprint

This preprint builds on previous studies demonstrating that the fat body acts as a sensor of starvation. Taken together with previous results, this provides evidence that the fat body acts as, in the words of the authors, a ‘sentinel tissue to detect changes in environmental conditions and to buffer the internal milieu from these changes’. The preprint is therefore an excellent example of how individual projects build up over time to shape our understanding of the bigger picture. Furthermore, the results in the preprint are complimented nicely by another preprint released at a similar time (link here) which also demonstrates that hypoxia sensing occurs in the fat body of Drosophila larvae. Both studies provide valuable insight into an area of research with increasing interest: the metabolic regulation of development.

Future directions and questions for the authors

Surprisingly, previously described hypoxia sensors REDD1 and HIF1a are not important in the suppression of TOR signalling in response to low oxygen in the fly larvae. What could alternative sensors be? In the discussion the authors suggest that interplay between the mitochondria and TOR could be responsible, for example through ROS or specific metabolites. Alternatively, could the lack of effect following deletion of REDD1/HIF1a homologs be a result of compensation from other upstream components of the TOR pathway?

An interesting observation from the study was that the downstream consequences of TOR repression are different in the context of hypoxia versus nutrient starvation. Specifically, when starved of oxygen, fat body lipid droplets increase in size, whereas when starved of food, fat body lipid droplets decrease in size. Since both physiological effects are mediated through TOR signalling, it would be interesting to know how the differential downstream effects of TOR repression are elicited. Could it be a dose-dependent effect, where for example moderate vs complete repression of TOR lead to alternate lipid droplet size outcomes? Alternatively, could alternate sensors of environmental conditions, which converge on lipid signalling, be responsible? Greater understanding of the signalling events both upstream and downstream of TOR could help yield insight into these questions.

The authors show that remodelling of lipid storage is responsible for the hypoxia tolerance, although exactly how this confers protection is not known. The authors suggest two possibilities: the droplets could act as a lipid store to fuel the energy-expensive process of metamorphosis, or they could provide protection from stress. Alternatively, could lipid droplets impact on endocrine signalling and orchestrate a whole-body physiological response? This could tie in with a potential parallel mechanism for tolerating hypoxia through inter-organ communication which is explored in the previously mentioned complementary preprint. For me, this downstream aspect is the most exciting avenue for future research since this is the most likely to be exploited for therapeutic benefit in diseases where hypoxia plays a negative role.

 

Posted on: 9th July 2018

Read preprint (No Ratings Yet)




  • Have your say

    Your email address will not be published. Required fields are marked *

    This site uses Akismet to reduce spam. Learn how your comment data is processed.

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the developmental biology category:

    Lineage tracing on transcriptional landscapes links state to fate during differentiation

    Caleb Weinreb, Alejo E Rodriguez-Fraticelli, Fernando D Camargo, et al.



    Selected by Yen-Chung Chen

    1

    Distinct ROPGEFs successively drive polarization and outgrowth of root hairs

    Philipp Denninger, Anna Reichelt, Vanessa Aphaia Fiona Schmidt, et al.



    Selected by Marc Somssich

    A direct and widespread role for the nuclear receptor EcR in mediating the response to ecdysone in Drosophila

    Christopher M Uyehara, Daniel J McKay



    Selected by Natalie Dye

    A metabolic switch from OXPHOS to glycolysis is essential for cardiomyocyte proliferation in the regenerating heart

    Hessel Honkoop, Dennis de Bakker, Alla Aharonov, et al.



    Selected by Andreas van Impel

    1

    Reconstruction of the global neural crest gene regulatory network in vivo

    Ruth M Williams, Ivan Candido-Ferreira, Emmanouela Repapi, et al.



    Selected by Hannah Brunsdon

    Functional characterization of Arabidopsis ARGONAUTE 3 in reproductive tissue

    Pauline E Jullien, Stefan Grob, Antonin Marchais, et al.



    Selected by Chandra Shekhar Misra

    1

    Single cell RNA-Seq reveals distinct stem cell populations that drive sensory hair cell regeneration in response to loss of Fgf and Notch signaling

    Mark E. Lush, Daniel C. Diaz, Nina Koenecke, et al.

    AND

    Distinct progenitor populations mediate regeneration in the zebrafish lateral line.

    Eric D Thomas, David Raible



    Selected by Rudra Nayan Das

    1

    Force inference predicts local and tissue-scale stress patterns in epithelia

    Weiyuan Kong, Olivier Loison, Pruthvi Chavadimane Shivakumar, et al.



    Selected by Sundar Naganathan

    Embryo geometry drives formation of robust signaling gradients through receptor localization

    Zhechun Zhang, Steven Zwick, Ethan Loew, et al.



    Selected by Diana Pinheiro

    Unlimited genetic switches for cell-type specific manipulation

    Jorge Garcia-Marques, Ching-Po Yang, Isabel Espinosa-Medina, et al.



    Selected by Rafael Almeida

    1

    Applications, Promises, and Pitfalls of Deep Learning for Fluorescence Image Reconstruction

    Chinmay Belthangady , Loic A. Royer



    Selected by Romain F. Laine

    Maintenance of spatial gene expression by Polycomb-mediated repression after formation of a vertebrate body plan

    Julien Rougot, Naomi D Chrispijn, Marco Aben, et al.



    Selected by Yen-Chung Chen

    1

    The coordination of terminal differentiation and cell cycle exit is mediated through the regulation of chromatin accessibility

    Yiqin Ma, Daniel J McKay, Laura Buttitta



    Selected by Gabriel Aughey

    1

    Embryo geometry drives formation of robust signaling gradients through receptor localization

    Zhechun Zhang, Steven Zwick, Ethan Loew, et al.



    Selected by Paul Gerald L. Sanchez and Stefano Vianello

    1

    Symmetry breaking in the embryonic skin triggers a directional and sequential front of competence during plumage patterning

    Richard Bailleul, Carole Desmarquet-Trin Dinh, Magdalena Hidalgo, et al.



    Selected by Alexa Sadier

    A SOSEKI-based coordinate system interprets global polarity cues in Arabidopsis

    Saiko Yoshida, Alja van der Schuren, Maritza van Dop, et al.



    Selected by Martin Balcerowicz

    1

    Close