Stephan Guyenet, Ph.D.: The Neuroscience of Obesity

Stefan Guyenet’s Background and Research

• Studied Biochemistry in college with a focus on neuroscience
• Completed PhD at the University of Washington studying neurodegenerative diseases
• Postdoc with Mike Schwartz at the University of Washington, focusing on obesity
• Interested in the neuroscience of obesity and its impact on society

Obesity Over Time

• Comparing modern humans to those from 1000 years ago, we are much fatter on average
• Obesity existed in the past, but prevalence was much lower
• First data on obesity in the US comes from Civil War veterans in 1890 and 1900 
  • Almost no obesity among middle-​​aged white men at that time
• More recent data from the 1960s shows an increase in obesity rates 
  • Around 12% of US adults had obesity at that time
• Progression of obesity has occurred at all levels, including more severe obesity (BMI over 35 or 40)
  Obesity and Adverse Health Outcomes
• Obesity rates have increased significantly over time 
  • In the 1960s, about 12% of adults were obese
  • Today, about 43% of adults are obese
• Association between obesity and poor health outcomes 
  • Ancient Greece and India recognized obesity as a health issue
  • Early 1900s insurance life tables showed shortened lifespans and greater risk of diseases for obese individuals
  • Controversial studies suggested there might not be a strong relationship between BMI and mortality (obesity paradox) 
    • Recent research suggests the paradox is likely an artifact of observational data
• Maximum attained weight method 
  • Looks at the heaviest a person has ever been and how it correlates with health outcomes
  • Shows a stronger difference between being lean and having obesity in terms of mortality
• Unintentional weight loss can be a sign of poor health 
  • Intentional weight loss through diet, lifestyle, and bariatric surgery has been shown to reduce all-​​cause mortality
• Semaglutide, a weight loss drug, has been shown to reduce all-​​cause mortality in people with type 2 diabetes 
  • It remains to be seen if this extends to people without type 2 diabetes

Obesity Rates Over Time

• Obesity rates spiked around 1980, but this is an average date of a multi-​​year survey
• It is difficult to pinpoint an exact time when obesity rates began to increase dramatically
• Nearly half of the US adult population now has a BMI above 30
  Survey on Obesity Rates
• Survey conducted between 1976 and 1984 
• Average year of the survey: 1978
• Sharp increase in obesity rates observed during this time
• Obesity rate increased from 15% to 43% in US adults

Lifetime Risk of Obesity and Type 2 Diabetes

• Lifetime risk of obesity: over 50% for US adults
• Lifetime risk of type 2 diabetes: significantly higher than current prevalence (10–12%)
• Prevalence of type 2 diabetes increased fivefold in the past 50 years

Obesity and Affluence

• No significant difference in obesity rates between bottom and top thirds of income distribution
• Differences emerge when considering sex and race
• All demographics in the US have experienced an increase in obesity rates

Role of the Brain in Obesity

• Brain generates behavior, which influences body fatness
• Hypothalamus contains a regulatory system for body fat mass
• Hypothalamic obesity caused by damage to the hypothalamus can lead to extreme obesity

Hypothalamic Obesity

• Closest experimental analog: VMH lesion in animals
• Lesion in the ventromedial hypothalamus replicates damage of hypothalamic obesity
• Consequences of hypothalamic obesity include hyperphagia (excess eating), loss of activity, and shutdown of metabolic rate
  Hyperphagia and the Hypothalamus
• Animals with damaged hypothalamus show extreme hyperphagia (overeating)
  • Gain weight rapidly, then plateau
  • Restricting calorie intake prevents most weight gain, but not all
• Hypothalamus is crucial for regulating body weight and fat storage

Leptin and the Lipostat

• Negative feedback system in the hypothalamus 
  • Measures levels of circulating hormone leptin, which is proportional to body fat mass
  • Hypothalamus has a “set point” for desired body fat
  • Defends against weight loss more effectively than weight gain
• Leptin is produced in adipocytes (fat cells) and secreted in proportion to body fat mass 
  • Levels can be affected by short-​​term energy balance (e.g., calorie restriction)
• Leptin receptors are found throughout the body, but most relevant ones for body weight regulation are in the brain, likely in the hypothalamus 
  • Controversy over the exact location of important receptors

Leptin Resistance

• Initially thought that people with obesity might have low leptin levels, causing the brain to perceive low body fat 
  • However, people with obesity actually have high leptin levels
• Leptin resistance: people with obesity require more leptin for the hypothalamus to be satisfied 
  • Exact cause is unknown (e.g., fewer leptin receptors, downstream signaling impairment, changes in cell-​​to-​​cell communication)
• Exogenous leptin administration does not significantly improve weight loss, suggesting that low leptin levels are not the primary issue

Heritability of Obesity

• Obesity has a heritability of 0.7, indicating a strong genetic component 
  • Genes have not changed significantly in the past 100 years, but obesity rates have increased
  • Suggests that susceptibility to obesity has been present for a long time and is highly preserved
    Genetics and Obesity
• Obesity has a heritability of 75% 
  • Variation in body mass index (BMI) between individuals is largely explained by genetics
• Genome-​​wide association studies (GWAS) help identify genes related to obesity 
  • Identified around 900 genetic variants that contribute to differences in BMI
  • These genes are complex and have small effect sizes
• Many obesity-​​related genes are heavily enriched for brain-​​related biology 
  • Similar to psychiatric diseases and educational attainment
  • Validates the importance of the brain in body fatness

Evolutionary Context

• 250,000 years ago, humans had similar priorities: 
  • Security from other tribes and animals
  • Acquisition of energy (food)
  • Reproduction
• Acquiring and storing energy was essential for survival 
  • Leptin serves as a signal for low energy levels, triggering the need to eat
  • High leptin levels don’t necessarily make you want to stop eating, as nature wouldn’t have cared about overeating

Energy Storage Efficiency

• The ability to store energy as fat is a remarkable evolutionary adaptation 
  • Efficient energy storage would have been beneficial in times of scarce food resources
• More research is needed to understand the genetics and efficiency of energy storage in relation to obesity
  Energy Storage and Body Fat
• Humans rely on storing fatty acids in white adipose tissue 
• Fat is a concentrated source of energy (9 calories per gram)
• Fat is hydrophobic, allowing for storage without hydration
• Energy storage is crucial for survival during times of food scarcity or illness
• Children with malnutrition have increased mortality rates
• Humans have more fat than our closest primate relatives (chimpanzees)

Ancestral Diets and Hedonic Properties of Food

• Hunter-​​gatherer diets were radically different from modern diets 
  • Less seasoning, sauces, and variety
  • Example: Hazda people eating charred, unseasoned meat
• Modern diets have a wider range of tastes and calorie-​​dense foods
• Reward circuits in the brain adapt to prefer calorie-​​dense, refined foods 
  • Exposure to preferred foods can devalue less preferred foods
• Transitioning from a modern diet to an ancestral diet can be challenging

Taste and Calorie Density

• Taste and calorie density are separate factors in food preference
• Table sugar and lard are examples of calorie-​​dense foods that may not taste good on their own
• Combining calorie-​​dense foods with other flavors can create highly palatable dishes
  Taste, Energy Density, and the Brain
• Sugar and fat are calorie-​​dense, but not very motivating on their own 
  • Optimal concentration of nutrients is not 100%
  • Bliss point: optimal concentration for enjoyment and reinforcement
• Ice cream combines sugar and fat, hitting multiple bliss points 
  • Foods associated with strong cravings and loss of control overeating often contain carbohydrate and fat combinations
• Ancestors prioritized calorically dense food, protein, and sodium 
  • Dopamine-​​mediated reinforcement prioritizes certain types of nutrients
  • Brains and bodies wired around energy acquisition
  • Neuropod cells in the small intestine detect nutrients and send signals to the brain

Why Ribeye Isn’t Overeaten

• Meat is not usually cited as a food associated with strong cravings and loss of control overeating 
  • Meat is about 75% water, so calorie density is not especially high
  • Meat does not have carbohydrates, so it lacks the fat-​​carbohydrate combination associated with loss of control around food
    High Protein Diets and Carnivore Diet
• Protein-​​specific appetite demonstrated in many species 
• Bodies want to get enough protein but not too much
• High protein diets can lead to reduced overall calorie intake

Carnivore Diet

• Anecdotal evidence of weight loss
• Zero carbohydrate, high protein, low variety
• Eliminates highly processed, calorie-​​dense foods
• Some plant compounds can be harmful, but cost-​​benefit analysis needed
• No randomized controlled trials on the impact of the carnivore diet on weight

Biochemical Changes on Carnivore Diet

• Shift towards ketogenic metabolism due to low carbohydrate intake
• Changes in blood lipid values (e.g., LDL cholesterol increase)
• Individual responses vary; some people experience large increases in LDL cholesterol
• Elevated LDL cholesterol raises red flags for long-​​term cardiovascular risk

Treating Elevated APO B

• Some patients only improve on carbohydrate-​​restricted diets
• If elevated LDL pattern develops, options are to abandon the diet or treat elevated APO B
• Using modern medicine to achieve the best of both worlds
• Dietary ideology can lead to irrational beliefs and ignoring potential health risks
• Cardiovascular disease is a major risk and should not be ignored
  Diet and Adiposity
• Stubborn ideologies in dieting 
  • Restrictive plant-​​based diets can lead to micronutrient and protein deficiencies
  • Carnivore diets and regenerative agriculture
• Energy balance, carbohydrates, insulin, and adiposity 
  • Carbohydrate-​​insulin model 
    • Diet and environment impact insulin signaling
    • Insulin signaling impacts body fatness
    • Fattening process leads to elevated calorie intake and possible decline in metabolic rate
  • Energy balance model 
    • Body fatness is regulated by energy intake and expenditure via the brain
    • Adipose tissue receives excess energy, not the driver of the process
    • Does not consider all calories identical in terms of impact on body fat
• Set point and lipostat regulation 
  • Set point can change based on dietary and environmental variables
  • Change in set point is not a durable resetting, but a modification due to a different environment
  • Maintaining the change can maintain the effect, but if the change goes away, the effect goes away
    Window of Vulnerability for Weight Gain
• Greatest window of vulnerability for weight gain is unclear 
• Potential for most people to gain weight at almost any point in life
• Intrauterine environment may play a role in obesity risk 
  • Evidence (not strong) suggests children of women who underwent bariatric surgery have lower obesity risk than children of women with similar weight who did not undergo surgery

Weight Loss and Maintenance Strategies

• For individuals with obesity (BMI 30–35), consider medical treatment (e.g., somaglutide) 
  • Seeing an obesity medicine specialist is recommended
• For individuals who want to lose a few pounds or are overweight, focus on controlling nonconscious brain signals 
  • Control food environment (sensory cues, food accessibility, effort barriers)
  • Choose foods with lower calorie density and higher protein content
  • Be mindful of portion sizes and avoid overeating due to external cues

Factors Affecting Satiety and Food Intake

• Complex system with multiple signals contributing to satiety and satisfaction 
  • Stomach distension, nutrient composition signals from the small intestine, sensory detection of food properties
• Calorie density, protein content, and palatability of food affect satiety
• Unclear how much external cues (e.g., constantly refilled bowls) affect long-​​term weight maintenance
  Carbohydrate Insulin Model vs. Energy Balance Model
• Carbohydrate insulin model: growth regulated by hormones, affecting energy intake 
  • Example: children eating more during growth spurts
• Energy balance model: easier to explain with experimental data 
  • Balance of energy intake and expenditure determines weight gain/​​loss
• Not mutually exclusive; both models may contribute to understanding obesity

Importance of Understanding Mechanisms

• Better understanding of mechanisms can lead to more targeted, effective treatments 
  • Example: semaglutide, a weight loss drug developed based on biological mechanisms
• Understanding mechanisms can also lead to insights in other fields, such as cardiovascular medicine

Insulin and Body Fat Distribution

• Genome-​​wide association studies show: 
  • Body mass index (BMI) largely regulated by the brain
  • Body fat distribution more related to insulin signaling
• Energy partitioning may play a role in obesity, but it doesn’t fully explain the phenotype

Diet Composition and Weight Gain

• Diets high in both fat and carbohydrates lead to weight gain 
  • Example: standard American diet
• Diets low in either fat or carbohydrates can lead to weight loss 
  • Example: ketogenic diet, potato diet
• Hedonic component (taste) and ubiquity of food choices may contribute to weight gain
• Animal studies show similar patterns in weight gain/​​loss based on diet composition

Speculation on Diet Composition and Weight Gain

• The combination of fat and carbohydrates in the standard American diet may contribute to obesity
• Cultural adaptation and industrialization may lead to diets high in both fat and carbohydrates
• Further research needed to understand the mechanisms behind diet composition and weight gain
  Empirical Observations on Diet Extremes
• Low carbohydrate and low-​​fat diets increase metabolic demands 
  • Body works harder to synthesize glucose or fatty acids
  • Effects of hundreds of calories a day observed in very low-​​fat or low-​​carb diets
• Food with both carbohydrate and fat is more appealing and motivating to eat 
  • Possible explanation for reduced food intake in extreme diets
  • Food has less implicit value to reward regions of the brain

Red Pen Reviews

• Nonprofit organization that reviews popular nutrition books 
  • Provides numerical scores for scientific accuracy, reference accuracy, and helpfulness
  • Allows for apples-​​to-​​apples comparison between books
• Takes 40–100 hours per book, with 14 reviews published since 2019 
  • Aiming for 6–8 reviews in 2021
• Eight reviewers, with some doing the majority of reviews and others rarely doing one
• Books selected based on sales, social media engagement, and author influence 
  • Examples: The Carnivore Code, The Volumetrics Diet, Eat, Drink and Be Healthy, Eat Fat, Get Thin
• Surprises and insights from reviewing books: 
  • Credentials not always a reliable indicator of information quality
  • State of popular nutrition books may be worse than initially thought
  • Fact-​​checking and fresh eyes on content are crucial for accuracy
    Podcast Transcript Summary
• Authors should be open to acknowledging mistakes in their published works 
  • Publishers do not impose a filter on the contents of books
  • Authors should seek expert opinions for each chapter
  • Accepting that a small percentage of the content may be wrong is important for growth
• Red Pen Reviews: a method to help authors write better books 
  • Random citation checks, criteria for healthfulness and scientific accuracy
  • Provides a resource to help improve information quality from the beginning
• Good faith debates between experts in a field are beneficial 
  • Forces people to be sharper in their thinking
  • Helps theories align better with experimental evidence
  • Understanding both sides of a debate is crucial for growth and learning