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

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

Dr. Zachary Knight (00:00:00)

  • Dr. Zachary Knight is a professor of physiology at the University of California, San Francisco, and an investigator with the Howard Hughes Medical Institute.
  • His research focuses on homeostasis, particularly hunger, thirst, and thermoregulation.
  • Brain circuits determine how much a person is likely to eat before they start eating.
  • Dr. Knight explains the biological mechanisms for satiety, the sense of having had enough food.
  • Dopamine plays a surprising role in food craving and consumption, countering common beliefs.
  • GLP-1 (glucagon-like peptide-1) is a hormone involved in regulating blood sugar levels.
  • Novel drugs like Ozempic and Mounjaro, which target GLP-1, are effective in reducing body weight.
  • Dr. Knight explains the discovery of GLP-1 and the development of these drugs.
  • The mechanisms behind how these drugs work and why they are effective are discussed.
  • These drugs represent the next generation of treatments for obesity, diabetes, and related syndromes.

Thirst and Its Relationship with Food and Salt Intake [N/A]

  • Water consumption is closely linked to food consumption.
  • Sodium intake, water intake, and food intake are interconnected.

Conclusion [N/A]

  • The discussion provides a comprehensive understanding of hunger, thirst, salt intake, and modern weight loss drugs.
  • Dr. Knight, a world-class researcher in these fields, shares valuable insights and knowledge.

Sponsors: BetterHelp, Helix Sleep & Waking Up (00:02:38)

  • Dr. Huberman emphasizes that this podcast is separate from his teaching and research roles at Stanford.
  • The podcast aims to provide free science-related information to the general public.
  • Today's episode is sponsored by BetterHelp, Helix Sleep, and Waking Up.
  • Dr. Zachary Knight is welcomed to the podcast.

Hunger & Timescales (00:07:07)

  • The regulation of food intake by the brain involves two systems: a short-term system and a long-term system.
  • The short-term system operates on the time scale of a meal (10-20 minutes) and controls the size of a meal.
  • The long-term system operates on the time scale of weeks to months to years and tracks levels of body fat.
  • The short-term system is localized to the brain stem, while the long-term system is localized to the hypothalamus.
  • The brain stem controls the size of a meal by sensing signals from the gut, such as gastric stretch and hormones like CCK.
  • The hypothalamus tracks overall energy reserves and body fat levels and modulates the brain stem circuits that control meal size to match long-term energy needs.
  • Dopamine is a neurotransmitter that is involved in the reward system of the brain.
  • Dopamine is released when we eat food, and it signals the brain that we have received a reward.
  • This positive reinforcement encourages us to continue eating, even when we are not hungry.
  • Dopamine also plays a role in addiction, as it is released when we use drugs or alcohol.
  • This can lead to a cycle of addiction, as we continue to use drugs or alcohol in order to experience the dopamine rush.

Body Fat, Leptin, Hunger (00:11:28)

  • Leptin, discovered by Jeff Friedman in 1994, is a hormone produced by adipose tissue that signals the level of body fat to the brain.
  • Leptin levels increase as body fat increases and directly reflect body fat reserves.
  • The leptin receptor is found in brain regions that control appetite.
  • Weight loss causes decreased leptin levels, triggering a starvation response in the brain characterized by increased hunger, reduced energy expenditure, decreased body temperature, decreased fertility, and decreased spontaneous movement.
  • Leptin is part of a negative feedback loop from fat to the brain that regulates body fat reserves and hunger.

Leptin Resistance & Obesity (00:17:51)

  • Leptin is a hormone that signals the brain about body fat and energy reserves.
  • Obese individuals usually have high levels of leptin, not low levels.
  • This condition is known as leptin resistance, similar to insulin resistance in type 2 diabetes.
  • A clinical trial showed that leptin injections resulted in minimal weight loss in obese individuals.
  • People with lower starting leptin levels lost more weight with leptin than those with higher levels.
  • Leptin could potentially be useful in treating obesity among individuals with low leptin levels or after significant weight loss.
  • The pharmaceutical industry and economic factors have hindered the development of leptin as a drug for obesity treatment.
  • There is a possibility that leptin could be revisited as a treatment option in the future, especially with the success of GLP-1 drugs and the increasing number of people losing significant weight.

Hunger, Food Foraging & Feeding Behaviors, AgRP Neurons (00:20:52)

  • AgRP neurons in the hypothalamus are crucial for the repetitive phase of feeding, such as searching for food.
  • AgRP neurons are linked to forebrain circuits involved in motivation, not directly to motor circuits.
  • AgRP neurons express receptors for leptin, a hormone that signals body fat reserves, and leptin inhibits AgRP neurons.
  • AgRP neurons in the brain predict how much food an animal will eat in an upcoming meal based on sensory signals from the body, such as the sight and smell of food, palatability, hunger level, and accessibility of the food.
  • Artificially stimulating AgRP neurons prevents the decrease in activity and causes animals to eat continuously, indicating that these neurons control both foraging and eating.
  • The exact purpose of hunger in biology is not fully understood, but it may be involved in satiety, reducing repetitive drive, allowing the transition to consummatory behavior, and preparing the body for a meal through cephalic phase responses.

Dr. Zachary Knight: The Science of Hunger & Medications to Combat Obesity (00:00:00)

  • Dr. Zachary Knight is a neuroscientist who studies the science of hunger and obesity.
  • He is the author of the book "The Science of Hunger".

AG1 Sponsor (00:30:26)

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  • Hunger is a complex process that is regulated by multiple hormones and brain regions.
  • The hypothalamus is a brain region that plays a key role in regulating hunger and appetite.
  • Ghrelin is a hormone that stimulates hunger, while leptin is a hormone that suppresses hunger.
  • Insulin is a hormone that helps regulate blood sugar levels and also plays a role in hunger.
  • The gut microbiome also plays a role in regulating hunger and appetite.
  • There are a number of medications that can be used to combat obesity.
  • These medications work by either suppressing hunger, increasing metabolism, or blocking the absorption of fat.
  • Some common medications used to combat obesity include phentermine, topiramate, and naltrexone.
  • These medications should only be used under the supervision of a doctor.

Body Weight & Obesity, Genes & POMC Neurons (00:32:15)

  • AGRP neurons, which are present in humans and express the leptin receptor, play a crucial role in regulating appetite and food intake.
  • People with anorexia nervosa exhibit an increased ability to perceive the caloric content of food.
  • The AGRP pathway is significant in humans due to its genetic implications.
  • AGRP and POMC neurons, which compete through neuropeptides, control appetite; AGRP neurons promote hunger, while POMC neurons promote satiety.
  • Obesity can have a genetic basis, with mutations in the AGRP-POMC pathway found in 10% of severely obese individuals.
  • Obesity is influenced by multiple genetic variations rather than single gene mutations.
  • Genes associated with body weight regulation are predominantly expressed in the brain, highlighting its role in controlling food intake and energy expenditure.
  • Twin studies suggest that approximately 80% of body weight variation between individuals is attributed to genetic factors.

Obesity, Genetics & Environmental Factors (00:39:54)

  • Obesity is a complex issue influenced by both genetics and environmental factors.
  • While genetics account for approximately 80% of individual variations in body weight, environmental factors can "unmask" latent genetic predispositions for weight gain.
  • The increase in obesity rates since the 1970s cannot be solely attributed to genetic changes, as human genetics do not change rapidly enough to account for such a significant shift in a short period.
  • In a controlled environment with restricted calorie intake, anyone can lose weight.
  • In a typical environment, an individual's propensity to gain weight is influenced by both genetics and environmental factors.

Whole Foods, Ultra-Processed Foods & Palatability (00:46:05)

  • The free availability of low-cost, high-calorie foods, especially ultra-processed foods, may contribute to obesity.
  • Ultra-processed foods have features that make people prone to weight gain.
  • Kevin Hall's experiment showed that people ate more and gained weight when consuming ultra-processed foods compared to whole foods, even when the foods were equally palatable.
  • Possible reasons for this include the optimized fat, sugar, and protein content of ultra-processed foods, as well as their lower volume and energy density compared to whole foods.

Increasing Whole Food Consumption, Sensory Specific Satiety & Learning (00:49:32)

  • Highly processed foods can confuse neural circuits and lead to overeating, while eating minimally processed whole foods separately can help regulate food intake.
  • A diet rich in protein, fish, eggs, vegetables, and fruit can aid in weight loss.
  • Sensory-specific satiety, which occurs when repeated exposure to a specific flavor or taste reduces appetite for that flavor, can be achieved by simplifying the diet and reducing variety.
  • Food preferences are influenced by learning and experience, and the post-ingestive effects of nutrients can change preferences over time.
  • Ultra-processed foods may disrupt the learning process about nutrient content, leading to impaired appetite regulation and overconsumption.
  • Medications for obesity target different mechanisms, including appetite suppression, reduced food intake, and increased energy expenditure.
  • Medications should be used in conjunction with lifestyle modifications, such as a healthy diet and regular exercise, for effective and sustainable weight management.
  • Neurons in the gut and hormones produced during digestion, as well as neurons in the brain that control appetite, are tuned to macronutrient content.
  • Neurons controlling eating and cessation of eating respond to amino acid content, essential fatty acids, and carbohydrate that replaces depleted glycogen.
  • Eating serves the purpose of replacing essential nutrients, with sensory cues indicating potential nutrient content.
  • Circuits controlling hunger are primarily calorie-specific, responding equally to sugar, fat, or protein with equal calories.
  • Protein is the most strongly defended macronutrient, with deprivation leading to protein hunger.
  • Sugar and fat intake are not strongly defended, as they can be interchanged with other macronutrients.
  • Sodium chloride (salt) is also essential, with deprivation leading to an innate salt appetite.
  • Salt appetite and protein appetite are the most strongly regulated at the level of macronutrients.

Dr. Zachary Knight: The Science of Hunger & Medications to Combat Obesity (00:00:00)

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Challenges of Weight Loss: Hunger & Energy Expenditure (01:03:58)

  • The body naturally resists weight loss by increasing hunger and decreasing energy expenditure, making it difficult to maintain.
  • While some individuals can successfully lose weight and keep it off, most struggle to do so.
  • Behavioral regulation, such as avoiding alcohol and adopting a healthy diet, can aid in weight loss maintenance.
  • Losing weight reduces energy expenditure, requiring individuals to consume fewer calories to maintain their new weight compared to someone of the same height and weight who has never been obese.
  • Researchers conducted a study using SGLT2 inhibitors, drugs that cause weight loss without the individual's awareness, to accurately measure energy expenditure and food intake.
  • The study found that for every two pounds of weight lost, hunger increased by approximately 100 calories per day, indicating that increased hunger is the primary challenge in maintaining weight loss.

GLP-1 Drug Development, Semaglutide, Ozempic, Wegovy (01:09:50)

  • GLP-1, a hormone produced in the intestine, regulates blood sugar and appetite.
  • GLP-1 analogs, like semaglutide (Ozempic) and liraglutide (Victoza), are used for diabetes treatment and have the side effect of suppressing appetite and promoting weight loss.
  • Exenatide, derived from lizard venom, was the first GLP-1 drug approved for diabetes treatment.
  • Liraglutide, an engineered GLP-1 compound with a longer half-life, was approved for weight loss in 2014 and can cause nausea as a side effect.
  • Semaglutide, initially approved for diabetes in 2017, has shown promising results in combating obesity, with clinical trials demonstrating significant weight loss, up to 16% of body weight within a year.

GLP-1 Drugs: Muscle Loss, Appetite Reduction, Nausea (01:19:03)

  • Weight loss from dieting or taking anti-obesity drugs can result in muscle loss, but resistance training and a high-protein diet can mitigate this.
  • The reduced muscle mass from weight loss may be offset by the loss of body fat, especially in the elderly.
  • Anti-obesity drugs primarily work in the brain stem, where the blood-brain barrier is weaker, allowing them to enter the brain.
  • These drugs reduce appetite by activating neurons in the nucleus of the solitary tract and cause nausea by activating neurons in the area postrema.
  • Medications for obesity target hormones and peptides in the gut and brain to reduce hunger and promote weight loss.
  • Some medications block fat absorption in the gut, while others increase the feeling of fullness.
  • Medications can be effective for weight loss but should be used with a healthy diet and exercise.

Pharmacologic & Physiologic Effects; GLP-1 Drugs, Additional Positive Effects (01:23:24)

  • GLP-1 agonists, drugs that increase GLP-1 levels, have shown promise in reducing alcohol consumption and providing other unexpected health benefits beyond weight loss.
  • GLP-1 agonists have a good safety profile, with large clinical trials showing their effectiveness and safety.
  • Semaglutide, a GLP-1 agonist used for weight loss, has shown promising results in reducing the risk of heart attacks, strokes, and all-cause mortality, even before significant weight loss occurs.
  • Semaglutide's effects may be due to anti-inflammatory properties that suppress out-of-control inflammation.
  • Pharmaceutical companies often extend patents on drugs by finding new clinical uses, preventing generic versions from entering the market and maximizing profits.

GLP-1-Plus Development, Tirzepatide, Mounjaro, AMG 133 (01:30:14)

  • Pharmaceutical companies are developing GLP-1 receptor agonists for weight loss.
  • Eli Lilly's tirzepatide (Mounjaro) is a dual agonist of GLP-1 and GIP, leading to greater weight loss and fewer side effects compared to semaglutide (Ozempic).
  • Eli Lilly is also developing a triple agonist of GLP-1, GIP, and glucagon, which has shown promising results in phase 2 trials, with participants losing 25% of their body weight.
  • Amgen's AMG 133 is a dual agonist of GLP-1 and GIP that inhibits the GIP receptor, leading to weight loss.
  • AMG 133 is an antibody with a longer lifetime in the blood compared to other GLP-1 receptor agonists, allowing for monthly injections and sustained weight loss.
  • The field of obesity drug discovery was previously avoided due to safety concerns, such as the fenfen debacle, where a diet drug caused cardiac issues and deaths, leading to its withdrawal from the market.

Alpha-MSH & Pharmacology (01:34:49)

  • Alpha-MSH, produced by the POMC gene, and AgRP neurons, located in the hypothalamus, have opposing effects on body weight regulation.
  • Alpha-MSH inhibits food intake, while AgRP neurons promote it.
  • Both Alpha-MSH and AgRP neurons converge at the melanocortin 4 receptor (MC4R), which plays a crucial role in body weight regulation.
  • Efforts to develop Alpha-MSH-based drugs for weight loss have been limited due to side effects such as increased blood pressure.
  • Manipulating the short-term energy balance system in the brainstem can also affect body weight, challenging the previous belief that only the long-term system in the hypothalamus could influence weight regulation.
  • The long-term hunger regulation system involving Alpha-MSH, AgRP neurons, and POMC has been challenging to target pharmaceutically.
  • There may be a renewed interest in targeting this pathway due to the success of GP1s, which could potentially be used in combination with hypothalamus-centered leptin-based drugs for weight loss and maintenance.

Dopamine, Eating & Context (01:40:41)

  • Dopamine is involved in motivation, learning, and adaptation to light, not just pleasure.
  • Dopamine plays a crucial role in motivating individuals to engage in effortful tasks to obtain food and learning associations between external cues and food availability.
  • Dopamine is involved in a slower time scale learning process that links the sensory experience of eating to the post-ingestive effects of food.
  • Dopamine is associated with wanting something, not necessarily liking it.

Dopamine & Learning, Water Content & Food (01:46:01)

  • Dopamine plays a role in the body's post-ingestive responses, connecting sensory cues associated with food to the consequences for the body.
  • Different populations of dopamine neurons respond to internal signals, such as the presence of nutrients in the stomach and intestine, and blood rehydration when thirst is satiated.
  • The activation of these dopamine neurons reinforces the connection between the flavor of food and its post-ingestive effects, helping individuals learn about the effects of what they eat.
  • Thirst is a learned behavior for many animals, including rabbits, who primarily obtain water from food and only drink water during specific times of the year.
  • Animals must learn which foods are rehydrating, as they cannot simply look at a food and determine its water content.
  • Dopamine neurons are activated when the blood is rehydrated, which is critical for animals to learn that food is rehydrating.

Salt, Water & Thirst (01:53:23)

  • Thirst, salt appetite, and hunger are controlled by separate systems in the brain.
  • Dehydration can lead to decreased food intake as the body prioritizes fluid balance.
  • Thirst and the desire for salt are closely linked to maintain blood composition.
  • Sensitive osmosensors in the body detect changes in blood osmolality and trigger thirst.
  • A 1% increase in blood osmolality can be perceived as thirst, and extreme discomfort occurs at a 10% increase.
  • Fluid homeostasis involves both the desire to drink and the function of the kidneys, which control salt reabsorption and water replenishment.
  • B. Anderson's experiments in the 1950s identified specific regions in the hypothalamus that act as osmosensors, triggering water consumption when salt is infused.
  • The regulation of fluid balance faces challenges similar to food consumption, with delays in the body's response to thirst.
  • Neurons in the hypothalamus track water intake and compare it to blood osmolarity, predicting when blood levels will return to normal and stopping drinking accordingly.
  • Cooling the mouth can quench thirst as water is usually cooler than body temperature, and the sensation of coolness is associated with water consumption.
  • Drinking cold water when thirsty is highly rewarding and can be compared to fulfilling a critical need for water.
  • Hydration plays a crucial role in the body's system and can provide a unique sense of satisfaction that surpasses the pleasure derived from food consumption.

Hunger vs. Thirst (02:03:27)

  • Stimulating thirst neurons in mice creates a state of virtual thirst, which they actively avoid.
  • Stimulating hunger neurons makes food more attractive and the experience of eating more pleasurable.
  • Mice are more willing to endure hunger than thirst, suggesting different motivational mechanisms for the two.
  • Thirst is primarily driven by the unpleasantness of dehydration, while hunger is driven by the reward of food.
  • The thirst circuit is mostly located in the forebrain, specifically in the subfornical organ and the OVLT (organum vasculosum of the lamina terminalis).
  • The reason for this evolutionary separation of thirst and nutrient-sensing neurons is unclear.
  • There is an element of learning associated with thirst, but the neurons in the forebrain also directly sense changes in blood salt concentration and hormones like Angiotensin, which drive thirst.

Dieting, Nutrition & Mindset (02:05:46)

  • People's perception of food can significantly impact their satiety and enjoyment of the food.
  • Inaccurate or accurate descriptions of food can shape whether people find it good or bad and whether it leads to more or less satiety.
  • The human brain has a vast computational capacity to make predictions about nutritional states and how information can change expected physiological outcomes.
  • Flavor-nutrient conditioning experiments in humans show that people's expectations about food can influence their consumption and satiety.

Tools: Improving Diet & Limiting Food Intake (02:09:39)

  • Limiting the consumption of ultra-processed foods and increasing the intake of whole foods can help control food intake and promote satiety.
  • Adequate protein consumption is crucial for satiety and protein leveraging, preventing overeating.
  • Drinking water during meals does not affect digestive enzymes and can help differentiate between hunger and thirst.
  • Water provides a limited fullness signal compared to other fluids, as the rate of gastric emptying depends on calorie content.
  • The body's complex regulatory mechanisms, involving the hypothalamus, brainstem, and gut, ensure balanced and safe nutrient intake.
  • Natural selection explains why significant and long-lasting weight changes require substantial increases in peptide hormones like GLP-1.
  • The body's weight regulation system is tightly regulated.

Anti-Obesity Drug Development (02:14:15)

  • The pharmaceutical industry is reinvigorated to investigate anti-obesity drugs.
  • In five years, there will be various drugs with different side effect profiles and efficacies to choose from.
  • These drugs will adjust physiology and hunger, aligning with the understanding of basic biology.
  • Dr. Zachary Knight is a neuroscientist and obesity researcher at the University of California, San Francisco.
  • His research focuses on the neural mechanisms that control hunger and body weight.

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