#212 – The neuroscience of obesity | Stephan Guyenet, Ph.D.

Stephan Guyenet is a neuroscientist focused on the neuroscience of obesity and energy homeostasis.  He is the author of the book, The Hungry Brain and founder/ director of Red Pen Reviews. In this episode, Stephan explains how obesity has changed phenotypically over the course of human history as well as what might explain the dramatic increase in prevalence of obesity in the last few decades. He talks in depth about the role of genetics, the brain, and hormones like leptin play in the regulation of fat mass. He dives deep into two common theories of obesity—the carbohydrate-insulin model and the energy balance model and provides his take on which theory has stronger evidence. Additionally, he provides insights on how we’re hard-wired to think about food and the consequences of modern foods designed for maximal pleasure. Finally, he goes through the factors that affect body weight, set points, and provides takeaways for people wanting to take advantage of what we know about the brain’s role in regulating our body weight.

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We discuss:

• Stephan’s neuroscience background and his focus on the nuances of obesity [2:15];
• How obesity has changed for humans throughout history [8:00];
• The association between obesity and adverse health outcomes, the “obesity paradox,” and confounders when relating BMI to longevity [14:00];
• The sharp increase in obesity across demographics [23:30];
• The hypothalamus and its role in obesity [30:00];
• The role of the hormone leptin in obesity [40:00];
• The genetic component of obesity [46:30];
• Understanding the tendency of humans to store fat through an evolutionary lens [57:00];
• The hedonic aspect of food, and how the brain reacts to modern, highly-rewarding foods [1:03:30];
• How we are hard-wired to think about food [1:14:30];
• A review of the “Carnivore diet” [1:21:45];
• The energy balance model, carbohydrate-insulin model, and unifying the theories around adiposity [1:34:15];
• Body weight set points: a hypothetical comparison of two individuals [1:41:45];
• Takeaways for people who want to lose weight and keep it off [1:48:30];
• Evidence that favors the energy balance model of weight gain [1:56:00];
• The synergistic effect of fat and carbohydrates and observations that a low-fat diet or a low-carb diet can cause weight loss [2:04:30];
• Red Pen Reviews [2:11:00];
• More.

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Stephan’s neuroscience background and his focus on the nuances of obesity [2:15]

Stephan’s path to becoming one of the most thoughtful people on the nuances of obesity 

• Stepahn was a biochem major as an undergrad, but had neuroscience in mind 
  • His idea was that biochem would provide a foundation for going into neuroscience later
• He did his PhD with Al LaSpada at the University of Washington studying neurodegenerative disease
• He stayed at the University of Washington for a postdoc with Mike Schwartz 
• He has always been fascinated by the brain, but didn’t know which area of neuroscience he wanted to get into for a long time
• He became interested in neurodegenerative disease for a few different of reasons: 
  • 1 – They’re just absolutely horrible diseases
  • 2 – His grandmother had Alzheimer’s disease
• In grad school he was studying a class of neurodegenerative diseases called triplet repeat diseases
• The genetics of Huntington’s disease are complex and interesting
  • It’s non-Mendelian because the length of the CAG repeat actually changes intergenerationally
  • The weird thing about it is these CAG repeats are unstable in replication
    • Theycode for polyglutamine structures in the protein 
  • You tend to see an enlargement of these polyglutamine repeats from one generation to the next
    • So it has this really weird non-Mendelian pattern
  • The penetrance is pretty high, meaning if you have this repeat of a certain length, you are going to develop disease
    • But it’s not 100% fixed
• Stephan was studying a less common disease called SCA7, spinocerebellar ataxia type 7
  • Not many people have this disease
• He had always been interested in fitness and nutrition
• So when he started learning about the neuroscience of obesity during his PhD work, he got really into it
  • This was a way to satisfy his desire for impactful research
  • He realized there was a ton of information on this topic that was incredibly enlightening and not making its way to the public

At what point, finishing up your PhD did you connect with Mike?

• He was interested in obesity and wanted to stay at the University of Washington for personal reasons
  • Staying at the same institution after your PhD is atypical but he was not a big fan of the typical academic thing
• Mike’s lab was a really good fit
  • He was a postdoc with him until 2013
• Peter remembers meeting Stephan at a conference in 2012, 10 years ago

 

How obesity has changed for humans throughout history [8:00]

• Humans have been around for maybe 6 million years

What has changed over the last 1000 years in terms of our phenotype? 

• Thinking of body shape of people in modern, affluent societies (like the US) compared to a typical human 1000 years ago, we are much fatter
• 1000 years ago there was obesity among the wealthy, probably for similar reasons that we have obesity today
  • There is evidence of this from Egyptian mummies
  • Certainly the prevalence was much lower
• Just to be clear, we’re defining obesity in the most traditional way as a BMI (body mass index) of more than 30
  • The advantage of BMI is it’s really easy to measure and you can calculate it from these really simple measures that go back a long time
  • Unfortunately they didn’t have DEXA machines in 1890, which would’ve been a more informative way of looking at it

How BMI has changes in recent history

• 120-130 years ago only a few % of people (low single digits) had a BMI > 30
• More recently, we start to have really good data in the US in 1960 when the NHANES (national health and nutrition examination survey) began
  • The % of people who are obese by this measure has gone up from the late 1800’s to maybe 12% of adults in the US
• The category of extremely obese refers to a BMI over 35
  • There is class 1, class 2, and class 3 obesity; these correspond to a BMI of around 30, 35 and 40 (see the table below)

Figure 1.  Basic BMI categories.  Image credit: Wikipedia

• More recently, the median BMI has increased too
• The most extreme changes happened in the more severe obesity category
  • Very few people had BMIs > 35 in the earliest measures
  • Today 9-10% of adults have a BMI > 35

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