Dr. Zachary Knight: The Science of Hunger & Medications to Combat Obesity

Andrew Huberman・2 minutes read

The Huberman Lab podcast explores the biological mechanisms behind food cravings, satiety, and the brain circuits that influence eating behavior, discussing GLP-1 drugs, leptin resistance, and hunger regulation in detail. The podcast also delves into the roles of dopamine, thirst, and salt intake, highlighting the complexity of appetite control and potential pharmacologic approaches to obesity treatment.

Insights

Dr. Zachary Knight explores the biological mechanisms behind food cravings, satiety, and the brain circuits influencing eating behavior, focusing on homeostasis.
The role of dopamine in food craving and consumption is explained, highlighting its function in motivating action and learning about cues predicting food availability.
Glucagon-like peptide 1 (GLP-1) and related drugs like OIC and Monjaro are discussed for weight reduction, diabetes, and obesity treatment, showcasing their potential in appetite suppression.
Leptin, a hormone signaling body fat levels, and its receptor in the brain control hunger, with leptin resistance observed in obese individuals, impacting weight loss responses to treatment.
The brain's anticipatory circuits play a crucial role in predicting nutritional needs, with human brains having vast computational capacity compared to mice, influencing food perception and satiety.
The pharmaceutical industry's focus on anti-obesity drugs, particularly GLP-1 drugs, shows promise in catering to different metabolic conditions and hunger regulation, offering optimism for future weight management options.

Get key ideas from YouTube videos. It’s free

Recent questions

What is the role of dopamine in food cravings?
Dopamine motivates action and learning food cues.

Related videos

Summary

00:00

"Science-based tools for everyday health"

The Huberman Lab podcast discusses science and science-based tools for everyday life, hosted by Andrew Huberman, a professor at Stanford School of Medicine.
Dr. Zachary Knight, a professor at the University of California San Francisco and Howard Hughes Medical Institute investigator, focuses on homeostasis, particularly hunger, thirst, and thermoregulation.
Dr. Knight delves into the biological mechanisms behind food cravings, satiety, and the brain circuits that influence eating behavior.
The role of dopamine in food craving and consumption is explained, contrary to common beliefs about dopamine's function.
Glucagon-like peptide 1 (GLP-1) and related drugs like OIC and Monjaro are discussed for weight reduction, diabetes, and obesity treatment.
The podcast explores the relationship between thirst, water consumption, and food intake, as well as sodium intake's impact.
The episode provides insights into modern hunger, thirst, and salt intake understanding, along with the use of drugs like OIC, from a top researcher in the field.
BetterHelp, offering online therapy, is a sponsor, emphasizing the importance of therapy for overall health.
Eight Sleep's Smart mattress covers, aiding in temperature control for quality sleep, are highlighted, with a discount available.
Waking Up, a meditation app, is promoted for mindfulness practices, with a free trial offer.

14:01

Leptin: Hormone Regulating Appetite and Weight

In the 1950s, mutations causing extreme obesity and hyperphagia were identified on different chromosomes in mice.
Scientist Doug Coleman connected the circulations of two strains of obese mice to test for a circulating factor controlling appetite.
The OB strain, lacking a fat-produced hormone, lost weight dramatically when connected to the DB strain, which remained obese.
Coleman hypothesized that the mutations were in a hormone and receptor, later confirmed to be leptin and its receptor.
Leptin, exclusively expressed in fat, signals body fat levels, while its receptor in the brain controls hunger.
Leptin levels in the blood directly reflect body fat reserves, triggering a homeostatic response to starvation.
Leptin was initially seen as a potential diet drug, but clinical trials revealed leptin resistance in obese individuals.
Stratifying individuals by leptin levels showed varying weight loss responses to leptin treatment.
Leptin could be effective for those with lower leptin levels or post-weight loss to maintain weight loss.
Agrp neurons in the hypothalamus play a crucial role in feeding behavior, stimulating hunger and food-seeking actions.

27:03

Neurons predict mouse eating behavior accurately.

Neurons in the brain predict how much a mouse will eat before it starts eating based on the food's smell and appearance.
A simple analysis involves observing how these neurons react when the mouse sees and smells food, then correlating it with the amount the mouse eats later.
The drop in these neurons occurs within 3-4 seconds, indicating a predictive mechanism for hunger and thirst control.
Animals learn to estimate food content based on experience, hunger level, and food appearance, transmitting this information to brain circuits for satiation.
The neurons may start the satiation process before eating, transitioning from repetitive to consummatory behavior.
Stimulating these neurons continuously can lead the mouse to overeat, showing the complexity of hunger regulation.
The neurons may also be involved in preparing the body for a meal, triggering responses like insulin secretion and gut motility changes.
AG1 is a nutritional supplement providing essential vitamins, minerals, probiotics, and adaptogens for overall health and stress management.
AG1 ensures foundational nutrition alongside a balanced diet, enhancing energy levels, digestion, and sleep quality.
AGRP neurons in humans express the leptin receptor and play a crucial role in regulating hunger and satiety, with mutations in this pathway linked to severe obesity.

40:31

Genetics, environment, and processed foods impact weight.

Genetics play a significant role in body weight, with around 80% of body weight being heritable.
The environment can shift the distribution of body weights in a population, affecting the mean weight.
Genetics set the propensity for weight gain, while the environment can trigger it.
The availability and low cost of calories, especially in highly processed foods, contribute to weight gain.
Kevin Hall's research shows that ultra-processed foods lead to increased consumption and weight gain compared to whole foods.
Highly processed foods may confuse neural circuits, leading to overeating despite meeting caloric needs.
Eating minimally processed whole foods separately may help regulate food intake more effectively.
The brain learns to link taste, macronutrients, and calories with satiation, aiding in appropriate food consumption.
An understanding of nutrient content and the impact on satiation can guide healthier eating habits.
Consuming minimally processed whole foods may help align food intake with the body's energy requirements.

53:57

Dietary strategies for weight loss maintenance

Eating a diet of proteins like meat, fish, eggs, vegetables, and fruits for a few months, then gradually adding back starches based on food intake has helped overweight individuals lose weight and maintain it.
Simplifying diets to Whole Foods can engage sensory-specific satiety, reducing appetite due to less variety in the diet.
Learning plays a significant role in food preferences, with flavors and smells interacting with post-ingestive effects of nutrients to change perceptions.
Neurons in the gut and brain need to be tuned to macronutrient content for appetite control, focusing on essential amino acids, fatty acids, and carbohydrates.
Hunger circuits are primarily calorie-specific, with protein being the most strongly defended macronutrient, while sugar and fat intake are not as strongly regulated.
Element, an electrolyte drink, is highlighted for hydration and electrolyte balance, essential for brain and body functioning.
Body weight homeostasis involves the activation of agrp neurons when weight is lost, driving increased food consumption due to lower leptin levels.
Some individuals can successfully lose weight and keep it off by following specific dietary patterns, despite challenges in developing effective weight loss diets.
Behavioral regulation improves when sober, impacting the counterregulatory response to weight loss and energy expenditure.
Weight loss leads to a decrease in energy expenditure, with a reduction of about 30 kilocalories per day for every kilogram lost, highlighting the challenges of weight maintenance post-weight loss.

01:07:22

"Weight Loss Challenges and GLP-1 Discoveries"

Energy expenditure in individuals who have lost weight is approximately 25% lower than those who were never obese, leading to the term "reduced obese" for the former group.
It is uncertain whether this reduced energy expenditure is due to a naturally slower metabolism or a result of prolonged higher weight affecting the brain.
Studies have shown that this difference in energy expenditure does not return within a year after weight loss.
Kevin Hall conducted a study using SGLT2 inhibitors to indirectly measure food intake changes after weight loss without the participants realizing.
For every two pounds of weight lost, hunger increases by 100 calories per day, leading to a 30-kilocalorie decrease in energy expenditure and a 100-kilocalorie decrease in appetite.
Increased hunger is a significant factor in the difficulty of maintaining weight loss.
GLP-1, a hormone that suppresses appetite, was discovered in the bloodstream of hila monsters and has analogs in mice and humans.
GLP-1 works to suppress appetite by boosting insulin response to glucose in the blood, originating from the intestine.
GLP-1 drugs for diabetes were developed, with GLP-1 from hila monsters having a longer half-life and leading to weight loss.
Semaglutide, a GLP-1 analog with a half-life of seven days, has shown significant weight loss results in trials, with some participants losing up to 16% of their body weight in about a year.

01:20:03

"Obesity, Drugs, and Weight Loss Innovations"

Obese individuals often have enlarged calves due to the need to support their body weight.
Pharmaceutical companies are developing drugs to prevent muscle mass loss in obese individuals.
Weight loss induced by these drugs is primarily due to reduced appetite, affecting brain regions like the nucleus of the solitary tract and the area postrema.
Neurons in the area postrema are linked to nausea, potentially explaining side effects of certain drugs.
Drugs targeting the brain stem regions have limited access to the brain due to the weakened blood-brain barrier in those areas.
Certain foods or drinks may increase GLP-1 levels, but the appetite suppressive effects are unlikely to lead to significant weight loss.
GLP-1 agonists in drugs create pharmacologic effects at much higher concentrations than natural hormones in the body.
GLP-1 drugs have been shown to be safe and offer unexpected health benefits beyond weight loss, potentially due to anti-inflammatory effects.
Companies are extending patents on GLP-1 drugs by finding new uses or combinations, leading to competition in the pharmaceutical market.
Future developments include triple agonist drugs combining GLP-1, GIP, and glucagon for enhanced weight loss and energy expenditure, resembling a pharmacologic version of bariatric surgery.

01:33:31

"New Compound Sparks Interest in Obesity Treatment"

The Amgen compound activates the Gip receptor through an antibody, lasting longer in the blood than peptides like semaglutide, allowing for monthly injections resulting in significant weight loss.
In an initial trial, participants maintained weight loss for 6 months after stopping the injections, sparking interest in pharmaceuticals for obesity treatment.
The field of obesity drug discovery has seen a resurgence of interest, shifting from caution due to past drug safety issues to a focus on new possibilities.
The hypothalamus, OIC, and GLP1 pathways play crucial roles in appetite control, with niche communities exploring peptides like melanocyte-stimulating hormone for weight management.
Alpha MSH, a product of the POMC gene, influences feeding control through neurons in the hypothalamus, interacting with the melanocortin 4 receptor to regulate body weight.
Efforts to turn Alpha MSH into a drug have faced challenges due to side effects, including increased blood pressure, highlighting the complexity of targeting body weight regulation.
The short-term system in the brainstem and the long-term system in the hypothalamus, involving leptin, Alpha MSH, and AGRP neurons, control energy balance and body weight.
Pharmaceutical discoveries have shown that continuous stimulation of the short-term system can lead to weight loss, challenging previous beliefs that only the long-term system could regulate body weight.
Combining GLP1 drugs for weight loss with hypothalamus-centered drugs like leptin may offer a scientific approach to maintaining weight loss after initial loss.
Dopamine plays a role in motivating action and learning about cues predicting food availability, rather than pleasure from food taste, highlighting its importance in feeding behavior and motivation.

01:46:52

Dopamine and thirst influence learning and eating.

Learning occurs slowly due to the delay between tasting food and its effects on the body, driven by hormones released in the intestine.
Investigation into the role of dopamine in post-ingestive responses reveals different dopamine neuron populations responding to signals from inside the body.
Dopamine activation after ingesting food or fluids reinforces the connection between flavor and post-ingestive effects.
Thirst is a learned behavior, as seen in a study of rabbits in New Zealand that primarily obtain water from food.
Dopamine response correlates with blood rehydration, indicating a signal for animals to learn which foods are rehydrating.
Personal experiment alternating low water content and high water content meals found the former to be satiating and efficient.
Humans may confuse thirst and hunger, leading to overeating or undereating based on water content in food.
Separate brain systems control salt appetite, thirst for water, and hunger for calories, with interactions in cases like dehydration anorexia.
Thirst and salt desire are closely linked to maintain blood composition, with specific neurons acting as osmo sensors.
Experiments in the 1950s led to the discovery of brain regions with osmo sensors, regulating fluid balance and thirst responses.

01:59:57

Brain's Thirst Sensors Regulate Hydration Levels

Osmos sensors in the brain discovered by Bank Anderson help sense and regulate thirst and return to normal activity.
Drinking water can quickly quench thirst within minutes, with neurons in the brain playing a crucial role.
Neurons in mice, similar to those in humans, track water intake by receiving signals from the mouth and blood to predict rehydration.
Thirst neurons in the brain monitor the volume of water passing through the mouth and blood osmolarity to determine when to stop drinking.
The brain accurately predicts the amount of water needed based on signals from the mouth and blood, ensuring optimal hydration.
Cooling the mouth can alleviate thirst, as the sensation of water passing through cools the mouth, signaling potential rehydration.
Thirst neurons decrease in activity when a cold metal piece is placed on a mouse's tongue, showcasing the brain's response to cooling.
Thirst and hunger neurons function differently, with thirst being driven by negative reinforcement to avoid dehydration.
Human perception of food, based on descriptions like caloric density or nutritional value, can significantly impact satiety and taste experiences.
The brain's anticipatory circuits play a crucial role in predicting nutritional needs, with human brains having vast computational capacity compared to mice.

02:13:03

Regulating Nutrient Absorption for Weight Loss

Nutrients should not enter the intestine too quickly as it can be unsafe and unpleasant due to the limited speed at which the intestine can metabolize them.
The gut regulates the rate of emptying based on the type of substance, such as water or orange juice, showcasing a complex and efficient system of checks and balances for survival.
The strong regulation of the body's homeostatic systems makes it challenging to outsmart the system safely, requiring significant increases in peptide hormones like glp1 to see lasting changes in weight.
The pharmaceutical industry's focus on anti-obesity drugs, particularly glp1 drugs, shows promise with unexpected weight loss benefits and safety, leading to optimism for a future with a variety of drugs catering to different metabolic conditions and hunger regulation.

Try it yourself — It’s free.