The Fat of the Matter: To know a fly, To know ourselves #MetabolismMondays

All the world’s a metabolic dance, and we are merely moving to the rhythm !

Emerging perspectives in metabolism

This week, we delve into the story of Dr. Lianna W. Watt, a Leading Edge fellow and a postdoctoral researcher at Stanford University, who is passionate about unraveling the intricacies of metabolism and sex differences—one fly and mouse at a time. Driven by curiosity and a deep respect for basic science, Lianna has explored how diet can rewire the way male and female bodies store and break down fat. She’s worked across model systems—from Drosophila to mammals—always with an eye toward understanding how sex-specific metabolic regulation shapes health and disease. Keep reading to discover how mentorship, curiosity, and a few bags of mini eggs helped shape Lianna’s career—and why she believes that studying both sexes is fundamental biology, essential not only for understanding disease
and metabolism, but also for uncovering evolutionary principles. Check out all her work here .

What was your first introduction to the field of metabolism – what’s is your first memory?

It was actually a conversation with my future undergraduate thesis supervisor, Dr. Ian Dworkin at McMaster University. I was interviewing to join his lab as a summer research student and that was when I learned that changing the diet of flies can reduce how different male and female wing shape and size are. The idea that changing the diet could have such drastic effects on metabolism to the point that organ shape and size are altered is what first drew me into metabolic research.

Could you share your journey into studying metabolism and what inspired you to specialize in metabolic studies using Drosophila melanogaster?

My research journey in metabolism began in flies, and it was truly just luck. I was in a joint-major undergraduate program and part of the requirement was an undergraduate thesis project. I had always planned on going into medical school, so I was late to the game looking for a lab. But a new professor had just joined McMaster’s biology department (Ian), and he took a chance on me. I worked with Ian on understanding how the ratio of macronutrients, or nutritional geometry, affected how different male and female shape and size are using Drosophila wings as a model system. This summer research projected turned into an undergraduate thesis and is what made me fall in love with research. I ended up forgoing applying to medical schools and instead applied for graduate research programs.
From my time with Ian, I knew I wanted to do research in sex differences, continue using Drosophila as my model, and transition to a more biomedical research question. At the time, very few labs focused on investigating sex differences but there was a new lab at the University of British Columbia (UBC) that studied sex differences in metabolism and physiology in Drosophila. This was Dr. Elizabeth Rideout’s lab, and it was the perfect fit for what I wanted to do and is ultimately where I completed my PhD.

How has your transition from working in Drosophila to working in the mammalian system been?

After my PhD, my career goal was to open my own lab that used multiple model systems to bridge the gap between basic science and clinical research. This motivation was why I transitioned to a mammalian lab for my postdoc. The transition for me was fairly smooth as I had ~1yr experience with the Kieffer and Clee labs at UBC using mice. The main differences between using flies and mice for me was how you plan experiments. In flies, you can decide to do an experiment and have the flies ready to go in 1-2 weeks and you can simply do one experiment per cohort. However, with the mice, I would need to have experiments planned over a month in advance (quarantine, breeding, weaning etc) and because it took so much time to have the correct mice for an experiment, you had to maximize what experiments you would perform on each cohort. However, after joining a mouse lab, I quickly realized that I much preferred working with flies to mice. It turns out, I am a geneticist at heart and many of the genetic tools I was used to having in my arsenal in a fly lab did not exist in the mouse world yet. Additionally, while vertebrate model systems are incredibly important for basic research, there is an emotional toll associated with solely using mammalian models. My time in a mammalian lab also helped me realize that I was more interested in understanding the basic science underlying the regulation of metabolism rather than the discovery of new therapeutics to treat metabolic disease. This together with the development of an anaphylactic allergy to mice is what solidified my return to a Drosophila model system.

Tell us how you got interested in the field of nutritional and metabolic aspects of sex differences? How do you think the fields of studying sex differences and metabolism overlap – tell us about your interests in these areas? How have both the sexes evolved to respond to nutrition and metabolic stresses?

One of my motivators for wanting to study metabolism is that my family has a history of type 2 diabetes and obesity – I recently found out that I have a genetic variant that predisposes me to obesity. While starting in the sex differences world was by luck, I decided to stay in this field because I realized just how widespread yet understudied sex differences are (almost every phenotype has a sex difference). Historically, females were omitted from studies because they didn’t show the same phenotypes as males and there was this belief that sex hormones just complicated the data. We can learn so much new biology if we were to include both sexes since males and females form naturally dichotomous groups.
In the case of metabolism, sex differences can be found everywhere from the risk and prevalence of metabolic disease, the response to therapeutics, basal metabolic phenotypes (ie. fat accumulation, blood glucose levels), and the regulation of major metabolic signaling pathways such as insulin and GLP1 (Glucagon-Like Peptide-1). In the metabolism field, is it widely accepted that males and females are phenotypically very different but many studies still only investigate males because females tend to have much weaker responses to metabolic challenges such as high fat diet. To me, this is actually an extremely exciting phenotype. Why are females more protected from developing metabolic dysfunction in response to metabolic challenges? If we could figure out the mechanisms that allow females to be protected, these may be promising avenues for new therapeutics to reverse or alleviate metabolic disease.

Why do you find the basic science aspects exciting ?

I find basic science so exciting because it is the foundation of discovery. We first need to understand normal regulatory processes to understand how these processes become dysfunctional and lead to disease. By investigating how metabolism is regulated in healthy individuals and how these processes can go wrong form the foundation for the development of novel therapeutics to treat metabolic disease. Without basic science, the development of new therapeutics would be significantly hampered.

Why do you think understanding both males and female systems from a metabolic perspective is important? How is it relevant in today’s human health dynamic? Your work is focused on uncovering mechanisms explaining how sex differences in fat metabolism arise, identifying novel functions for metabolic genes and pathways that contribute to how males and females store and break down fat differently. Could you elaborate on the key findings and their implications for the field?

For many years, the metabolism field has known that males and females store and distribute fat differently, and that many metabolic diseases associated with abnormal fat storage hare a male-biased risk and prevalence. While there is a beautiful body of work investigating how sex determination factors (ie. sex chromosomes and sex hormones) establish these sex differences, we lack an understanding of the metabolic genes and metabolic pathways that act downstream of sex determination factors to contribute to the regulation of sex differences in fat metabolism.
My major findings during my PhD were 1) majority of lipid metabolism genes are sex-biasedly regulated, 2) the triglyceride lipase brummer (mammalian ATGL) acts in the somatic cells of the gonad and the neurons to regulate sex differences in fat storage and fat breakdown, 3) lipid droplets are normally present in the neurons (not just diseased states) and may be sex-biasedly regulated by brummer, and 4) the sex determination factor Transformer establishes sex differences in fat metabolism in flies via the sex-biased regulation of the adipokinetic hormone (Akh) signaling pathway. These findings represent novel functions of metabolic effectors and open the doors for interesting questions such as how lipid droplet dynamics in neurons are regulated and how does this impact whole-body fat metabolism, how sex determination factors regulate downstream metabolic effectors like brummer (bmm) and Akh. Also, ATGL inhibition is being investigated in mammals and humans as a potential therapeutic but my data suggests that inhibiting bmm/ATGL function will have greater effects in males than females, thus indicating that ATGL inhibition studies need to be performed in both sexes.

Your work intersects sex differences, metabolism and aging. How do you integrate these disciplines in your research, and what unique insights have emerged from this approach?

I tend to think of sex differences as a tool to understand metabolism. For example, my broad question is how does our brain respond to a high fat diet? Are there certain regions/neuronal populations that become more or less active? How are these high fat diet-induced changes different between males and females? In this way, studying sex differences sheds light on understanding the metabolic phenotype.

You work on sex specific hormonal regulation of lipid metabolism. How difficult were those experiments? Did you have to deal with midnight timepoints or require an army of undergrads/ long hours etc.?

I think the difficulty of any experiment or technique really varies from person to person. For example, molecular techniques such as colorimetric assays and qPCRs came easily to me but I always found imaging more challenging. Having more hands on deck was always a huge bonus because it meant larger or more experiments could be done. For example, if it was just me, I could maybe screen ~5 RNAi lines simultaneously. But if I had 2-3 trainees helping me, that could easily go up to 15-20 RNAi lines. Training and mentoring the next generation of scientists has always been very important to me and I’m really grateful that I had the opportunity to work with so many amazing budding scientists – many of which are recognized as authors on my publications.
As for late night timepoints – this only happened for specific experiments, namely whether circadian rhythm affected the sex difference in fat storage. For this set of experiments, I had a timepoint every 4 hours for a 24 hour period. My philosophy is that I would never have my trainees do something that I wouldn’t do myself so for these experiments, I collected all the samples. While napping on a desk wasn’t the most comfortable, I didn’t mind because I knew this data was important and it wasn’t a regularly occurring experience. I also had the added benefit of Liz (my PhD supervisor) buying me a huge bag of mini eggs to help me make it through the night haha

Building upon your findings in sex-specific fat metabolism and hormonal regulation, what are your upcoming plans? Are there particular metabolic pathways or hormonal regulators you aim to investigate further?

My plans going forward are actually to take a broader look at metabolic function. I mentioned earlier that one well-known sex difference in mammalian metabolism research is that females do not develop metabolic dysfunction to the same degree as males in response to metabolic challenges such as high fat diet. For example, in response to HFD, male mice will develop glucose intolerance and gain more body weight/fat mass than females, and male mice will also have worse cognitive defects after chronic high fat diet than female mice. This together with my previous work suggests that the brain plays a major role in regulating the sex-biased response to HFD. Thus, one major question of my postdoctoral work is what are the brain-wide effects of HFD on neuronal metabolic function? My goal is to use live, volumetric 2-photon imaging in conjunction with genetically-encoded metabolite sensors to investigate how HFD alters neuronal metabolic flux and function in male and female brains.

How are you planning to integrate insect and mammalian models to bridge basic science and therapeutic research?

My current plan for the future is to establish a lab that integrates neurobiology and molecular biology to study how the brain responds to external metabolic stressors (such as chronic diet perturbations or fasting) to regulate whole-body energy homeostasis. My primary model system will likely be Drosophila and any findings that are particularly exciting, I will also investigate in mammalian models, thus allowing me to bridge the gap between invertebrate and vertebrate systems.

What changes have you seen in the research community in regard to studying sex differences ? How do you think scientific paradigms around studying both sexes will evolve in the coming decades? Are we moving toward a more nuanced understanding, or do you see potential pitfalls?

When I started my PhD, I felt that the community acknowledged that sex differences exist but did not think they were important enough to dedicate an entire research project to. In the last decade, I have definitely seen this mentality shift to more appreciation for studies that uncover the mechanisms by which sex differences are established and controlled. We’ve also seen changes in regulations where studies need to justify why they only study one sex and more acknowledgement that what we learn from studying males may not necessarily apply to females. Studies are now also more transparent regarding which sexes are used for specific experiments. This shift towards more studies including both sexes or detailing which sex is used can only be a good thing as it provides us with more data and thus a better understanding of the normal regulatory processes of metabolism. However, even sex is a spectrum with many variations in sex chromosomes. As the field of sex differences evolve, I believe it will become increasingly nuanced until the whole spectrum of sex can be studied to the best of our ability.

How you see the future of metabolism evolve with the new upcoming tools – what techniques have you used and which tools are you most excited about ?

One roadblock that has hampered the discover of new signaling pathways that control metabolism is the identification of ligand-receptor pairs. With the advent of AI-assisted protein structure prediction (eg. AlphaFold, AlphaLigand), the ability to predict receptors for a known ligand or vice versa significantly speeds up our ability to identify metabolic molecular mechanisms. Recent advances have even been able to use AI to predict new drug therapies for example. I think AI will be a really strong tool in a basic scientist’s arsenal.

What role does curiosity play in your life, both within and outside of science? 

Curiosity is a huge part of being a scientist – the desire to know more can really motivate your work. There’s this misconception that scientists know all there is to know about a subject, but if you maintain a child-like sense of wonder or curiosity, you’ll see that there is so much left to learn. When I spend time with my nieces and nephews, my favorite part is hearing their questions because really, every question can lead to a research project. I recently told my niece that our hair and our nails are made of the same thing. She asked me why and I didn’t know. But that could be a budding scientist’s first foray into research.

Were there any pivotal moments that shaped your career path? What advice would you offer to students and early-career scientists interested in exploring the intersections of metabolism and inter-organ communication?

My pivotal moment was joining the Dworkin lab for my undergraduate thesis project – if I hadn’t, I very likely wouldn’t have fallen in love with research and would have gone to medical school.
For anyone interested in research, I would suggest that you think broadly and approach your research question from many angles. While my main focus is on energy metabolism, you can study this from many different points of view such as a neuroscientist or a mathematician.

How do you maintain a balance between your rigorous research activities and personal life? Are there hobbies or practices you find particularly rejuvenating?

I learned the hard way that if you don’t make time for things outside of research, you will burn out. My life outside the lab is equally as important as my time in the lab so I put more effort into planning my work week/month and experiments to maximize the likelihood that I won’t need to be in lab on the weekends or late into the night. Sometimes, that’s just impossible and I work the occasional weekend/late night. Outside the lab, I’m a huge book lover and spend a lot of time reading. I also love to cook and bake. I’ve also been an avid yogi since my undergraduate days so I try to maintain this hobby by going to yoga practice first thing in the morning – I find that waking up early is more reliable than leaving lab at the same time every day.

If you hadn’t embarked on a career in biological research, what other profession might you have pursued, and why?

I’d love to open a cozy bookstore/café hybrid! Somewhere people could get lost among the shelves with a mug of tea. Or maybe that’s just what I want to do haha !

Anything you’d want to highlight ?

I was just selected as one of 2025’s Leading Edge fellows. This is a group of women and non-binary early career scientists that support one another in obtaining R1 faculty positions and tenureship. I’m really proud to be a part of this community to elevate women and non-binary individuals in science.

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