David Mangelsdorf is Professor and Chair of the Department of Pharmacology at UT Southwestern and an Investigator of the Howard Hughes Medical Institute. His research focuses on nuclear receptor regulation of metabolism. Dr Mangelsdorf will present his Medal Lecture at SfE BES Online 2020, on Monday 16 November. Learn more about his research, upcoming presentation and career in our interview.

Tell us a little about your career

I became Chair of Pharmacology in 2006, which I inherited from Alfred Gilman, who discovered G proteins and won the Nobel Prize for it. At first I was reluctant to become Chair but then I realised that the role isn’t just about holding together a department but also mentorship and recruiting great, young talent. Here the Chair is given quite a bit of latitude, you keep the Chair as long as you want it and are doing a good job – really you are a benevolent dictator, where you make the rules but they are for the benefit of everyone.

I wanted to be able to juggle three balls, the department, my research lab and my family. Our department has a great administrative team to support me in managing the department and I run a joint lab with Steve Kliewer. We did our PhDs together and have now been working together since 2002.

What inspired you in to endocrinology?

As a graduate student I was in Mark Haussler’s lab, which discovered the hormonal form of vitamin D and its receptor. Mark Haussler was a great scientist and mentor who supported and inspired my work. I then went on to investigate orphan nuclear receptors.

What are you most proud of in your career so far?

The accomplishment of understanding the role of orphan nuclear receptors. I was involved in deorphanising several nuclear receptors.

I am most proud of the discovery of the farnesoid X receptor (FXR), as it has become an important therapeutic target for biliary cholangitis and more recently nonalcoholic steatohepatitis, a type of fatty liver disease. Our work showed how FXR affected liver and lipid biology and to see it now being developed into a therapeutic target is one of my most significant accomplishments.

Steve Kliewer and I are a team, we worked on FGF hormones together, to establish what they do. We worked out the FGF signaling pathway and showed the important role of FGF19 and FGF21 in liver function and metabolism.

Please tell us a little more about what you will be presenting during your Medal Lecture at SfE BES online 2020?

I will be focusing on how FGF21 signals from the liver to the brain to regulate metabolism and nutrient stress, which has implications for obesity, diabetes and the response to alcohol. You can think of FGF21 as a stress hormone, it responds to nutrient stress and two of its most common inducers in people are sweets and alcohol. FGF21 signals to the brain to trigger an anhedonic response – intended to tell you to stop consuming it.

If you give animals a choice between water and water with something sweet or alcoholic added, they will choose the sweet or alcohol up to a point but when FGF21 is administered they stop and return to only drink the water. However, if you knock out the FGF21 signal entirely, they not only keep drinking the sweet or alcoholic water but they drink it even more. FGF21 also encourages more water drinking, presumably to encourage hydration when consuming sugar or alcohol.

Why do you think people eat and drink to excess then?

This is more of an addictive or conditioned behavior but there is no evidence, yet, that FGF21 can affect this in people. We know FGF21 is active in the human brain and perhaps even in areas that control addictive behavior. It is possible that the human FGF21 pathway evolved to compensate for the intake of very sweet or alcoholic foods. We know that people who enjoy drinking, and who drink more, have more of a certain genetic marker in their β-klotho gene than teetotalers. β-klotho is a co-receptor for FGF21. This may have evolutionary significance as alcohol is a natural preservative and there was an evolutionary advantage to having a little alcohol in things like water, to prevent disease. When you start drinking, you might like a sip of beer or wine but would hate stronger alcohol like vodka. People condition themselves to drink more as they get a buzz from it.

Could the FGF21 pathway have therapeutic applications for obesity and alcoholism?

There are very few things known to limit the intake of sugar and alcohol in humans, so there is potential therapeutic value in FGF21 but this needs much more investigation. However, human genetics do point towards a role for FGF21 in overdoing alcohol and sugar consumption.

How has the COVID-19 pandemic affected your research?

Significantly, I think like everyone else it has set us back. We thought it would be just 2 weeks lockdown back in March but even now we are not back to full working capacity. We do a lot of animal work, so we couldn’t do anything. Our long-term studies using animal models had to be stopped and that meant we had to cull colonies. So when we came back we needed to restart everything – in some studies it has set us back as much as 6 months to a year.

The other problem is the inability to interact directly with other people, either in a laboratory or at conferences.

What do you think about the move to virtual meetings?

Doing virtual talks is a terrible experience in my view, it is so artificial and the technology isn’t quite up to par yet. You really miss the human interaction.

The only benefit is saving money on travel and being able to be present at meetings you might not have been able to attend. I’ve enjoyed being at home with my family but do miss interacting with colleagues directly.

What do you enjoy most about your work?

Well, before COVID-19, I enjoyed interacting with the lab – I have an open door policy. I enjoy the element of discovery, I like to be inspired, to take bold steps, not to be afraid to ask a big question, and to go in new directions. I love learning about new areas, we have just started working in neurobiology.

What do you think are the biggest challenges in your field?

Specifically in my work it is the complexity of the central nervous system. It takes a long time to do thorough and careful investigation in the brain.

More generally, the lack of funding makes it difficult to take risks and move the field forward. Investigating new areas, defining new pathways and developing new models needs a lot of funding and a lot of time.

What do you think will be the next major breakthrough in your field?

To demonstrate whether FGF21 and FGF19 are viable therapeutic targets. When looking at treatments that are given long-term, there will always be problems. All drugs have side effects but the longer you are exposed to them the more likely adverse effects may occur. We need to establish if these targets are good for designing new treatments. Deciphering the neuroendocrine circuits of metabolism and behaviour is ongoing and will be key to establishing new therapeutic targets.

Any words of advice for aspiring endocrinologists?

You have to ask a big question to answer a big question. Don’t be afraid, if you want to make a difference, you have to take risks. As long as you are asking an important question, you are going to learn something – you shouldn’t spend time trying to put a round peg in a square hole, whilst losing sight of what the science is telling you.

For example, we were trying to find the ligand for a different nuclear receptor when we discovered the one for LXR. The graduate student had used a negative control that came up positive in her experiment. She was distressed that her experiment had failed but in fact she had inadvertently found the LXR ligand.

In the spirit of the times, my advice is that you should practice safely masking your face, but not your science!

You can hear David Mangelsdorf‘s Medal Lecture “FGF21 and Nutrient Stress: Eat and Drink, But Don’t Get Too Merry” on Monday 16 November at 13:40 GMT. If you haven’t already, register for SfE BES Online now!