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#212 – Stephan Guyenet, Ph.D.: The Neuroscience Of Obesity | The Drive with Peter Attia

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Key Takeaways

  • “More than half of U.S. adults will be classified as actually having obesity at some point in their life if the current context is maintained. You see the same thing with type 2 diabetes.” – Dr. Stephan Guyenet
  • There is no demographic in the U.S. adults where we have not gotten much fatter over the last few decades – regardless of income, education, or geography – we’re getting fatter than we were
  • Obesity is highly heritable (about 75%) and preserved
  • Differences in body fatness between individuals are primarily determined by differences in how the brain is constructed and operates
  • Any time you eat something sweet, that food substance causes neuropod cells in the gut to send parallel signals to the brain which activates dopamine and tells us to seek out and eat more sweet foods
  • Dietary tribal ideology can hold you back from finding the right foods for your body
  • The distribution of fat in the body is more related to insulin signaling; the total amount of fat in the body is related to energy intake
  • The types of foods most addictive are generally a mix of carbohydrates and fat in optimal concentration which triggers dopamine and activates seeking behavior
  • When it comes to nutrition, author credentials are not indicative of the quality of information and publishers do not fact-check – be diligent and unbiased in your review or check out Red Pen Reviews (free to public)


Stephan Guyenet, Ph.D. (@sguyenet) is a neuroscientist focused on the neuroscience of obesity and energy homeostasis. He is the Founder and Director of the nonprofit Red Pen Reviews, an organization that publishes informative and unbiased book reviews to help readers evaluate the information of health and nutrition books.

In this episode of The Drive, Peter Attia and Stephan Guyenet take a deep dive into obesity. They cover topics ranging from trends over time, to the role of genetics, hormonal factors, and theories of obesity. Peter and Stephan also provide insights on how we think about food, the consequences of modern food, and provide takeaways for people wanting to take advantage of what we know about the brain’s role in regulating our body weight.

Host: Peter Attia (@PeterAttiaMD)

Book: The Hungry Brain by Stephan Guyenet, Ph.D.

History Of Obesity & Population Trends

  • “If we’re comparing the body shape of people in modern affluent societies like the United States to what the typical human would’ve looked like 1,000 years ago, I think it’s clear we’re much fatter today on average with a much higher percentage of obesity.” – Dr. Stephan Guyenet
  • It’s not to say there was no obesity in the past – we can see obesity even as far back as Egyptian mummies, but it was rare and often an indicator of wealth
  • Traditional definition of obesity: BMI > 30
  • The first good data on population health started in the 1960s, but obesity had already gone up since the late 1800s – early 1900 when obesity rates were low (as indicated by Civil War veteran metrics)
  • In the earliest measures (1960s) obesity was around 12% in the U.S. among adults
  • Morbid/extreme obesity: BMI > 35
  • There are more significant changes in higher BMI ranges – we’re now approaching 9-10% of U.S. adults in the morbidly obese range
  • Between the late 70s to early 80s, the obesity rate started to climb
  • Today, about 43% of U.S. adults have a BMI of 30 or greater
  • There’s still a low prevalence of obesity in areas of food scarcity and less developed regions  

Obesity As An Indicator Of Health

  • In historical times, obesity was a marker of wealth
  • Obesity paradox: a series of studies showed the relationship between BMI and mortality to be controversial, with most mortality taking place in the “overweight” or low end of the obese range (but you’d expect mortality to be higher in the more extreme range)
  • Theory explaining obesity paradox: a lot of diseases and illnesses that lead to mortality come with weight loss (e.g., cancer, renal disease, Alzheimer’s, etc.) so the “paradox” is a casualty of the observational study design
  • BMI is a crude measure useful on population scale and for screening but take it with a grain of salt
  • Maximum attained weight method instead of BMI: compare current weight against the heaviest you’ve ever been and compare against health outcomes
  • Intentional weight loss does reduce all-cause mortality

Neurobiology Of Obesity

  • What does the brain have to do with obesity? The brain is the organ that generates behavior and contains a regulatory system for body fat (in the hypothalamus)
  • The hypothalamus engages physiological responses and is responsible for maintaining homeostasis
  • Hypothalamic obesity: tumors or damage to the hypothalamus causes extreme obesity
  • Hypothalamus as body fat monitor (“lipostat”): hypothalamus measures circulating leptin in the body and uses it to determine whether your body has as much fat as the hypothalamus wants it to and will react accordingly (e.g., regulation of energy expenditure, fat storage, hunger cues, etc.)
  • Setpoint can be modified but you have to maintain the change to maintain the effect
  • Leptin: made in adipocytes – in other words, the more body fat you have, the more leptin
  • Leptin in the bloodstream is correlated to fat mass and responsive to changes in energy balance (i.e., low-calorie diet for a few days will reduce leptin)
  • Leptin resistance: failure by leptin to perceive bodyfat so the hypothalamus thinks there’s not enough; contributes to obesity since the body requires more leptin to avert the brain’s starvation response

Heritability Of Obesity

  • Heritability: explains the differences between people that are due to genetics, not chance
  • The genes that regulate obesity have a heritability as high as 75% as seen in twin studies
  • High heritability of obesity explains why some stay thin while others struggle to maintain weight
  • Differences in BMI across individuals are genetically complex
  • Important markers of obesity studies: (1) it’s important to keep people in their natural state and study genes; (2) highly replicable; (3) objective since it’s not hypothesis-driven
  • People with obesity-promoting genes have a greater drive for food and lower satiety (but there have not been enough studies on this topic)
  • There’s some light evidence that there may be an influence of the intrauterine environment on obesity, meaning what’s going on with the mother while you’re developing in the uterus

Energy Balance

  • Energy density of fat: there are good reasons to have some body fat – energy, hydrophobic (don’t need to hydrate fat cells like glycogen), the relative weight of adipose tissue is low
  • The primary cause of mortality in children under 5 is strongly related to low body weight because there’s not enough energy storage in the body
  • Humans have a lot of fat storage compared to other animals
  • Carbohydrate insulin model: diet & environment impact insulin signaling – and – insulin signaling impacts body fatness which downstream leads to elevated calorie intake
    • In other words: the primary cause of fatness is adipose tissue increasing in fatness – increase in appetite and drive for food goes up to accommodate the reduction of circulating metabolic fuels caused by drive toward fatness 
  • Under the carbohydrate-insulin model – sleep disturbances or foods that trigger insulin are driving an environment, which is driving an increase in food intake
  • Energy balance model (basically opposite of carbohydrate-insulin model): input of fuels in the system leads to increase of circulating metabolic factors driving energy balance into fat cells
    • The energy balance model takes into consideration brain regulation of body fatness and appetite, but it’s regulated by energy expenditure via the brain

Modern Food Versus Ancestral

  • Our food and taste have drastically changed over time
  • Our ancestors took food out of nature and cooked it – nowadays our brains are set up to want better tastes (e.g., salt, seasoning, proper cooking, etc.)
  • Sugar and pure fat are calorie-dense
  • Bliss point: the optimal concentration for enjoyment and reinforcement (dopamine release)
  • The types of foods most addictive are generally a mix of carbohydrates and fat in optimal concentration which triggers dopamine
  • We don’t see foods in nature that trigger bliss point the same way as foods high in carbohydrate and fat
  • Dopamine-mediated reinforcement: our bodies are set up to respond to certain nutrients and create a motivation and learning response that prioritizes and sets the seeking of those foods
  • The preference for sugar-containing foods is a part preference, part “post-ingestive effect” by neuropod cells
  • Nerve cells (specifically called neuropod cells) in the gut are collecting information about what’s there and send that information up to the brain via the vagus nerve
  • Neuropod cells sense nutrients, particularly sugar, which activates areas of the brain that increase dopamine and cause you to seek out more of that food
  • It’s harder to overeat protein – our body wants it but to a certain limit

The Carnivore Diet & Weight Loss

  • Carnivore diet thesis: plants and almost everything is toxic except grass-fed products
  • Of course, the carnivore diet will lead to weight loss, in part because of calorie restriction
  • Near zero carbohydrate: the most fattening diets are rich in carbohydrates and fat – on carnivore, you’re eliminating most carbohydrates
  • Protein-packed: protein signals satiety
  • Reducing variety in diet so the body knows what’s going on
  • Cutting out processed foods: this component alone can lead to weight loss and prevent excess intake
  • Cost-benefit analysis: it’s true to some degree that some plants, whether inherently or in excess, can have adverse effects but the literature does not support the extreme nature of the carnivore diet – if you’re curious, monitor your blood and see how your body responds
  • Biochemical changes: a shift towards the ketogenic state, changes in positive and negative directions in blood lipids, LDL cholesterol & particle count can skyrocket, dyslipidemia in extremes – this is all dependent on the individual

Weight Loss Factors To Consider

  • For BMI 35 and higher experiencing loss in quality of life, it’s worth considering medical intervention (we have safe & effective weight loss drugs now)
  • Give the nonconscious brain signals consistent with your goals: (1) control sensory cues in the food environment; (2) be intentional about your eating and stop when you’re full; (3) know how many calories are in your food/meal (protein has the most satiety per gram)

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