How fructose drives metabolic disease | Rick Johnson, M.D.

**Peter Attia** (0:11)
Hey everyone, welcome to the Drive podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you wanna take your knowledge of the space to the next level. At the end of this episode, I'll explain what those benefits are, or if you wanna learn more now, head over to peterattiamd.com forward slash subscribe. Now, without further delay, here's today's episode. My guest this week is Rick Johnson. This will be a familiar name to a lot of you as he was a previous guest back in January of 2020 And we recently re-released that episode in preparation for this interview, which was carried out in November of 2021 Rick has authored over 700 scientific publications, as well as three books, The Sugar Fix in 2008, The Fat Switch in 2012, and his new book, Nature Wants Us to Be Fat, which is out February 8th, 2022
Rick is a professor of medicine and the chief of the renal division and hypertension at the University of Colorado, where he conducts research exploring the role of fructose in the development of obesity, metabolic syndrome and kidney disease.
Rick's initial episode was a really popular one, despite the technical nature of it. And that coupled with a bunch of follow-up stuff is really what prompted me to bring him back. In this episode, we talk about how the body can actually generate fructose from glucose to NOVO and the effect of circulating glucose and cell levels on activating this conversion. That's a pretty novel concept. That's not something that I certainly appreciated until very recently. Talk about the effects of fructose on weight gain by driving an increase in food intake. Talk about the decline in metabolic flexibility associated with aging and how factors such as sugar intake or menopause-associated hormone changes can alter the response to sugar across a lifetime. We'll talk again about pharmaceutical therapies on the horizon for blocking fructose metabolism and their potential use in treating metabolic syndrome, the impact of fructose metabolism and uric acid on kidney function and blood pressure. And we conclude with a discussion on vasopressin, a hormone that facilitates fructose's effect on weight gain and insulin resistance.
Again, a somewhat technical discussion, but I think Rick has a pretty good way of explaining technical things in such a manner that even if you don't have a background in the biochemistry, I think you can follow on really well. So without further delay, please enjoy my conversation with Rick Johnson.
Hey Rick, good to see you again.

**Rick Johnson** (2:49)
Great to see you too, Peter.

**Peter Attia** (2:51)
We had a lot of follow-up questions from our first podcast, which actually was probably about two years ago.
In addition to the other topics that I wanted to follow up on, we sort of asked listeners, we're gonna do another round two here, what do you have? So, so much of what we're gonna talk about today is a combination of things that I wanted to double click on, coupled with that and what others did. But I think a number of people have asked the question, hey, can you explain again, why is it that fructose metabolism is kind of unique from a nutrient standpoint in terms of creating this transient, intracellular energy deficit? This is something that becomes very important, and we get into sort of the metabolic effects of fructose.

**Rick Johnson** (3:34)
Absolutely. So just to reiterate what you're saying, all nutrients are there to produce energy. Any kind of food, we're using it to generate energy or ATP in our body, but there's a cost to producing energy. And so some energy is used to digest foods and some energy is used to metabolize foods.

**Peter Attia** (3:57)
It's the idea, the old adage, you have to spend money to make money. Now you're going to get that ATP back in spades if you just stay with the program.

**Rick Johnson** (4:04)
That's absolutely true.

**Peter Attia** (4:06)
All right. So let's talk now about fructose. And is fructose unique in what you're about to describe?

**Rick Johnson** (4:12)
Well, alcohol can also activate this process. And so alcohol can cause rapid ATP depletion as well.
But in terms of most nutrients, fructose is pretty unique. Yes.

**Peter Attia** (4:25)
Okay. So how does that work?

**Rick Johnson** (4:27)
Yes. So with fructose, the very first enzyme in fructose metabolism is called fructokinase. And this is going to become an important enzyme to remember. Its nickname is ketohexokinase or KHK, one of the key enzymes in fructose metabolism. It phosphorylates fructose at the one position. So it's fructose one phosphate. That enzyme will literally phosphorylate the fructose as soon as it sees it. It doesn't have any negative feedback. If ATP levels start to drop, that's fine for the fructose metabolism. That's what fructose metabolism is aimed at doing. And so if you have a large concentration of fructose, it's concentration dependent. If the fructose concentration is very low, there won't be as much ATP depletion and it may actually go undetected.