The neuroscience of obesity | Stephan Guyenet, Ph.D.

**Peter Attia** (0:11)
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Now, without further delay, here's today's episode.
My guest this week is Stephan Guyenet. Stephan is a neuroscientist and a passionate communicator about the science of primarily obesity, but many aspects of health. His research has focused on neurodegeneration early in his career, and then more recently the neuroscience of obesity and energy homeostasis. His scientific publications have been cited more than 3,600 times. He's the author of a book in 2017, The Hungry Brain. He's also the founder and director of Red Pen Reviews, which publishes informative, consistent and unbiased reviews of popular health and nutrition books.
He is a review editor at Frontiers in Nutrition. In this episode, we talk about his background and what led him to get to where he is today.
We talk about obesity and how it's changed phenotypically over the last thousand years, and specifically looking at US rates of obesity over the past probably 150 years. Talk about what the brain has to do with obesity, the role of leptin in the genes that regulate fat mass and obesity. Talk about the hedonic aspects of food and how our taste today is different than obviously what our ancestors tasted, and how energy and caloric density relate to taste and how we potentially select foods. We discuss the carnivore diet and Red Pen's review of the carnivore diet. We speak about the energy balance model, the carbohydrate insulin model, and unifying theories around adiposity. So without further delay, please enjoy my conversation with Stephan J.
Hey Stephan, thanks so much for making time. I've been looking forward to this for such a long time, probably since I started a podcast, which has been now we're coming up on four years. I always knew we'd have to sit down. So I'm glad we're finally doing this, albeit not in person, but that's more an artifact of my laziness. I think a lot of people listening to this will be familiar with you and your work, but I think a number of people won't be. So let's tell people a little bit about your path to where you are now, which is sort of being one of the most thoughtful people on the nuances of obesity. What did you study in college? Were you a neuroscience major?

**Stephan Guyenet** (2:45)
Biochem, but I had a neuroscience in mind when I was doing biochem. My idea at the time is that it would provide a foundation for going into neuroscience later, which I'm not sure that reasoning really works out so well, but it worked out okay in the end.

**Peter Attia** (3:01)
And did you go straight from your undergrad to Mike Schwartz's lab? Or did you do your PhD with Mike Schwartz or a postdoc?

**Stephan Guyenet** (3:08)
Postdoc.

**Peter Attia** (3:09)
Okay, so where did you do your PhD?

**Stephan Guyenet** (3:10)
PhD was with Al Espada at the University of Washington studying neurodegenerative disease.

**Peter Attia** (3:16)
Interesting, so tell me about that. Was that a detour that was always part of the plan or at that point were you not yet fully interested in obesity?

**Stephan Guyenet** (3:25)
I think more the latter. So I've always been fascinated by the brain, but I didn't know which area of neuroscience I wanted to get into for a long time. I became interested in neurodegenerative disease for a few different reasons. One, they're just absolutely horrible diseases. And two, my grandmother had Alzheimer's disease.
And in grad school, I was studying neurodegenerative disease, but I wasn't studying Alzheimer's disease. I was studying a class of neurodegenerative diseases called triplet repeat diseases that includes Huntington's disease or polyglutamine repeat diseases would be another name for them. So Huntington's disease is the most common.
That's the most common heritable neurodegenerative disease.

**Peter Attia** (4:11)
It's an absolutely awful disease with almost 100% penetrance, correct? I mean, it's a deterministic gene?

**Stephan Guyenet** (4:17)
Well, it's actually more complex and interesting than that. It's the genetics of it are real interesting because they are non-Mendelian because the length of the CAG repeat actually changes intergenerationally. The weird thing about it is there's these CAG repeats that code for polyglutamines, polyglutamines stretches in the protein, they are unstable in replication. And so what you tend to see is an enlargement of these polyglutamine repeats from one generation to the next. So it has this really weird non-Mendelian pattern. Okay, you asked specifically about penetrance. I think the penetrance actually is pretty high. So in other words, if you have a polyglutamine repeat in the wrong protein of a certain length, yes, very high likelihood you're gonna develop the disease. But like anything, it is not 100% fixed. But I don't think we really understand what makes it not fixed. I was studying one of the less common ones called SCA7, Spino Cerebellar Ataxia Type 7 You know, it's an interesting disease. It's a neurodegenerative disease with some relevance to other more common neurodegenerative disease. I used to joke that there were probably more scientists studying it than people with the actual disorder. I don't think that's actually true, but I think you get the point of the joke.