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

In this episode, my guest is Dr. Zachary Knight, Ph.D., a professor of physiology at the University of California, San Francisco (UCSF), and Howard Hughes Medical Institute (HHMI) investigator. We discuss how the brain controls our sense of hunger, satiety, and thirst. He explains how dopamine levels impact our cravings and eating behavior (amount, food choices, etc) and how we develop and can change our food preferences and adjust how much we need to eat to feel satisfied.
 
We discuss factors that have led to the recent rise in obesity, such as interactions between our genes and the environment and the role of processed foods and food combinations. We also discuss the new class of medications developed for the treatment of obesity and diabetes, including the GLP-1 agonists semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro). We discuss how these medications work to promote weight loss, the source of their side effects, and the newer compounds soon to overcome some of those side effects, such as muscle loss.
 
Dr. Knight provides an exceptionally clear explanation for our sense of hunger, thirst, and food cravings that translates to practical knowledge to help listeners better understand their relationship to food, food choices, and meal size to improve their diet and overall health.

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Dr. Zachary Knight

Timestamps
00:00:00 Dr. Zachary Knight
00:02:38 Sponsors: BetterHelp, Helix Sleep & Waking Up
00:07:07 Hunger & Timescales
00:11:28 Body Fat, Leptin, Hunger
00:17:51 Leptin Resistance & Obesity
00:20:52 Hunger, Food Foraging & Feeding Behaviors, AgRP Neurons
00:30:26 Sponsor: AG1
00:32:15 Body Weight & Obesity, Genes & POMC Neurons
00:39:54 Obesity, Genetics & Environmental Factors
00:46:05 Whole Foods, Ultra-Processed Foods & Palatability
00:49:32 Increasing Whole Food Consumption, Sensory Specific Satiety & Learning
00:58:55 Calories vs. Macronutrients, Protein & Salt
01:02:23 Sponsor: LMNT
01:03:58 Challenges of Weight Loss: Hunger & Energy Expenditure
01:09:50 GLP-1 Drug Development, Semaglutide, Ozempic, Wegovy
01:19:03 GLP-1 Drugs: Muscle Loss, Appetite Reduction, Nausea
01:23:24 Pharmacologic & Physiologic Effects; GLP-1 Drugs, Additional Positive Effects
01:30:14 GLP-1-Plus Development, Tirzepatide, Mounjaro, AMG 133
01:34:49 Alpha-MSH & Pharmacology
01:40:41 Dopamine, Eating & Context
01:46:01 Dopamine & Learning, Water Content & Food
01:53:23 Salt, Water & Thirst
02:03:27 Hunger vs. Thirst
02:05:46 Dieting, Nutrition & Mindset
02:09:39 Tools: Improving Diet & Limiting Food Intake
02:14:15 Anti-Obesity Drug Development
02:17:03 Zero-Cost Support, Spotify & Apple Follow & Reviews, YouTube Feedback, Social Media, Neural Network Newsletter

#HubermanLab #Health #Obesity

[hubermanlab]

Thank you for watching. If you enjoyed this topic and episode, please click the "like" button and subscribe to our channel here on YouTube. Thank you for your interest in science!

[StoicAurelius]

For those who have trouble limiting their food intake like me, let’s watch and do better. Happy Monday everyone

[karenmcrobb]

Dr Zachary Knight was literally an encyclopedia! I hope he returns to the podcast in the future. What a gracious guest and so smiley too!

[TheteaonGLP]

I lost 76 pounds in 6 months on GLP-1/GIP. I am NOT losing muscle now. I get monthly DEXA scans. Next scan is TUESDAY last month I gain 6.0 pounds of muscle and lost 10.6 pounds of fat. Long time listen first time comment. This is great. I’m really interested in the science. I only kept my muscle because of you! You content is amazing. Thank you for making sure at the end of this LAST weight loss journey I am healthy and lean not just skinny fat. I’m actually increasing my BMR each month by about 48-52 cals a day based on my DEXA scans. You are my hero Dr Huberman. Glad I found you your changing my life!❤

[AaronStone-vjnl]

Dr. Huberman, this is AMAZING. Thank you so much for having this discussion. Your work in bringing zero cost to consumer information on topics such as this are breaking down barriers and letting laymen learn and be curious. Thank you.

[dameanvil]

7:11 🧠 Overview of topics: dopamine, vagus nerve, brain-body interactions in hunger and eating.
7:19 🍽 Question about the brain's role in hunger, meal decisions, and self-regulation of eating.
7:31 🔄 Brain's dual-system approach: short-term (meal-related) and long-term (body fat levels) regulation.
8:00 🐀 Key experiment: Zombie rat study showing brainstem's role in meal size regulation.
8:39 ⏳ Short-term signals: Gastric stretch and hormones like CCK influence meal termination.
9:52 🏋‍♂ Long-term regulation: Hypothalamus tracks energy reserves and modulates brainstem circuits.
11:34 🛢 Body fat tracking: Brain uses body fat levels as an energy reserve signal.
12:18 💧 Comparison with thirst: No reserve of water, unlike fat's role in energy storage.
12:55 🔬 Discovery of leptin: Hormone from fat cells indicating body fat levels, cloned in 1994.
13:37 🧬 Obese and diabetic mice: Key experiments showed mutations affecting hormone and receptor.
14:36 🩸 Hormone-receptor interaction: Circulating factor experiment revealing leptin's role.
16:18 📉 Leptin feedback loop: Loss of fat decreases leptin, increasing hunger and reducing energy expenditure.
17:53 💊 Leptin resistance: High leptin levels in obese individuals lead to reduced effectiveness of leptin treatments.
19:45 🔄 Potential future use: Leptin therapy for weight maintenance after weight loss, despite current underuse.
21:04 🔬 The discussion is about the brain's role in hunger, eating behavior, and food consumption decisions.
21:41 🥗 Feeding behavior is divided into appetitive (searching for food) and consummatory (eating) phases.
22:08 🧠 Forebrain circuits, especially the hypothalamus, are crucial for the appetitive phase, while brain stem circuits manage the consummatory phase.
22:27 🌟 AGRP neurons in the hypothalamus are vital for driving the desire to find and consume food when hungry.
23:07 🚶 AGRP neurons motivate food-seeking behavior but don't directly control movement circuits; they set goals that the animal then pursues.
23:43 🐭 Stimulating AGRP neurons in mice triggers voracious eating, while silencing them leads to starvation, underscoring their critical role in hunger.
24:22 🔄 AGRP neurons express leptin receptors, and leptin inhibits these neurons, linking body fat levels to hunger control.
25:00 🧪 AGRP neuron activity drops significantly and rapidly when a hungry mouse sees food, indicating they predict food intake.
26:39 🔮 AGRP neurons predict food consumption based on sensory information and previous experiences, starting the satiation process before eating begins.
27:39 🍽 AGRP neurons' activity drop signifies a transition from foraging to eating and might be involved in preparatory responses for digestion.
29:47 🥩 Satiation involves multiple brain mechanisms that integrate new information to regulate eating behavior.
32:15 🧬 AGRP neurons exist in humans and play similar roles in hunger and satiety, influenced by genetics and experience.
37:10 🍔 Mutations in the AGRP-POMC pathway are linked to severe obesity, highlighting the genetic basis of body weight regulation.
39:02 🧬 Genetic studies show most genes associated with body weight regulation are expressed in the brain, emphasizing the brain's role in food intake and energy expenditure.
39:57 🧬 The debate on obesity often centers on genetics versus environmental factors, but it's likely a combination of both.
40:38 🍽 Embracing a variety of tools, from lifestyle changes to pharmaceuticals, can aid in managing obesity effectively.
41:09 🌍 Environmental changes, like the availability of highly processed foods, play a significant role in the rise of obesity rates.
46:09 🥦 Whole foods are less processed and typically more satiating, which may help regulate food intake better than ultra-processed foods.
49:32 🧠 Learning and sensory-specific satiety influence food choices, potentially favoring diets rich in minimally processed foods.
58:55 🍲 Neuronal responses to food focus more on calorie intake rather than specific macronutrients like sugar or fat.
1:04:03 🍽 When individuals lose weight, hunger may increase due to heightened activity in certain neurons, driven by lower leptin levels and a biological urge to regain lost weight.
1:05:05 🚫 Most people struggle to maintain weight loss long-term, despite various dietary approaches. Success stories often involve sustained behavioral changes rather than specific diets.
1:06:20 📉 After weight loss, energy expenditure decreases, which can make maintaining a lower body weight challenging, even years after initial weight loss efforts.
1:08:19 🧠 Research on energy balance shows that for every 2 pounds of weight lost, appetite increases by about 100 calories per day, potentially thwarting long-term weight management efforts.
1:09:50 💊 GLP-1 drugs like semaglutide exploit biological pathways to suppress appetite effectively, offering substantial weight loss benefits in clinical trials.
1:19:08 🏋‍♂ Weight loss from GLP-1 drugs tends to prioritize fat loss over muscle loss, but maintaining muscle mass can be supported by higher protein intake and resistance training.
1:23:29 🍽 GLP-1 Agonists are pharmacologic in nature, offering much higher hormone concentrations than natural physiologic changes induced by food.
1:24:57 🚫 Food and drinks generally do not increase GLP-1 to the levels seen with pharmacologic agents like drugs.
1:25:23 📉 Physiologic effects of GLP-1 modulation by food are minor compared to the significant effects seen with pharmacologic GLP-1 agonists.
1:26:55 💊 GLP-1 agonists like semaglutide have been extensively studied since 2005, demonstrating safety and unexpected health benefits beyond weight loss.
1:30:14 🏷 "GLP-1 plus" drugs like tirzepatide combine GLP-1 agonism with other mechanisms, offering enhanced weight loss efficacy and fewer side effects.
1:31:50 🌟 Future obesity treatments include triple agonist drugs combining GLP-1, GIP, and glucagon, potentially offering substantial weight loss without surgery.
1:34:21 🩺 Interest in obesity drug discovery has surged due to recent successes, contrasting with earlier cautionary tales like the fen-phen debacle.
1:36:24 🧠 Niche interest in melanocortin pathway peptides for appetite control may lead to new FDA-approved treatments in the future.
1:39:25 🔄 Short-term manipulation of the brain's appetite control system through GLP-1 agonists contrasts with the historically challenging long-term approaches like targeting leptin.
1:41:24 🧠 Dopamine plays a crucial role in motivating animals to work for food, especially when the effort required is high. Even low levels of dopamine can influence willingness to engage in tasks for food rewards.
1:42:54 📚 Dopamine facilitates learning about external cues that predict food availability (like seeing a McDonald's sign). This learning occurs rapidly and is crucial for survival.
1:46:03 🥤 Dopamine also contributes to slower learning processes related to the sensory experience and post-ingestive effects of food, reinforcing associations between taste and nutritional benefits.
1:47:30 🌟 Dopamine neurons respond to internal signals like nutrient levels in the stomach and bloodstream, aiding in the learning of which foods are beneficial based on physiological effects.
1:51:05 🧂 The desire for salty foods, like Parmesan cheese, can stem from the body's need to maintain sodium levels. Thirst and salt appetite are closely linked mechanisms that help regulate body fluid and blood composition.
1:53:28 💧 Thirst and salt appetite are distinct from hunger for calories but can interact in situations like dehydration, where the body prioritizes fluid balance over food intake.
1:55:10 📡 Separate brain circuits regulate salt appetite, thirst, and hunger, each responding to different signals and maintaining essential bodily functions.
02:03:32 🥤 Thirst neurons in animals are more strongly motivated by negative reinforcement to avoid dehydration, while hunger neurons primarily enhance the pleasure and attractiveness of food.
02:04:28 🧠 Thirst is largely processed in the forebrain, emphasizing its role in aversion to unpleasant states, whereas hunger is more about the rewarding aspects of food consumption.
02:05:56 🧠 Knowledge and perception significantly influence human eating behaviors and physiological responses, demonstrating how informational cues about food affect satiety and enjoyment.
02:09:30 🍽 Recommendations from physiology and neuroscience suggest focusing on whole foods, adequate protein intake, and debunking myths about fluid consumption during meals.
02:12:10 🚰 Drinking water during meals does not significantly dilute digestive enzymes or interfere with food digestion; it primarily helps differentiate thirst from hunger signals.
02:14:19 💊 Advances in anti-obesity drugs like GLP-1 show promise due to their effectiveness, safety profile, and potential for diverse therapeutic options in managing metabolic conditions.

[HereForToday]

Please do episode 2 with Dr. Zachary Knight! He had so much fun. His brain was going so fast he could barely keep up with it, even speaking at lightning speed- and he has a great smile. You both were great

[storagephone]

Please Do Another Episode on Autism treatment. Please vote up so my message reaches Prof Huberman.

[HereForToday]

love all these smart scientists who genuinely love science and can communicate that to regular peeps

[Arsh_]

Please make an episode on Skin. I have been suffering all my life with this organ. It’s too much information out there which is contradicting to each other. Appreciate your work, and totally trust it.

[sarahbarnwell]

I feel like this guest is that type of smart that's just so rare and special. I felt like the whole time he was trying to make what he was saying digestible (pun intended) for the general public. Bravo to both of you for a great episode!

[Minnasification]

"Just push away from the table" has just been eviscerated before my eyes. Truly one of your best yet. Dr Knight is such a great communicator. I was riveted the entire time. This is a must watch for anyone who struggles with their weight, cares for someone who does, and those who still promote the moralization of obesity.

[amannaithani]

Thanks Dr Huberman for the good you are doing tirelessly and helping so many people. I have been following you much before this podcast and implementing many of your protocols in my life and seeing great results. Gratitude and Respect.

[katiegeorge]

A request for a future episode: it’s not your typical topic, but could do a guest series with veterinarians on pet health? Questions on proper nutrition, whether to spay/neuter, physical and mental simulation etc. on dogs and cats would be super interesting to us animal owners listening

[az]

9-5 daily fasting was difficult at first. I found my ideal eating timeframe after a month or so of tweaking. Then I just decided that being hungry was ok. Just like being afraid (long time rock climber) and still acting is ok. Even beneficial. Essential, in fact.
Weight/height balanced 59 yr old female. HRT changed my body - no more joint pain!
And walking!
Sleep.
But it all started with intermittent fasting, thank you AH.

[KeithM-htzc]

TLDR: Don’t lose hope, you can lose weight and keep it off.
I lost 70 lbs 5 years ago and have kept it off. I wish I could have jumped in the conversation around the 1:06:00 mark, but I think when you lose significant weight, genetically and neurologically your body does not change to then become a system that now no longer becomes overweight. My hypothesis for how I’ve kept the weight off and how others have is that we’ve created a different neurological behavioral system that is more successful than the hunger systems/pathways that lead to us controlling our environment and response to that environment better. For me, it’s tracking calories because my hunger/satiety signals are untrustworthy, misleading, or maybe “confused”. Other people manage the inputs from the environment in other ways, by controlling what types of stimulus they are exposed like avoiding carbs or eating certain times of day or via other methods. Bottom line is there is a way to successfully keep off weight, but you have to create a new, and more successful, system to outcompete the hunger/satiety systems/pathways that works for you. Don’t lose hope.

[neilbaumann]

Dr. Knight talks so quick and concise. Its nice to see young doctors taking such an interest in society.

[vernekelley]

1. Question: with such increased doses, how does this affect a diabetic? Is there more hypoglycemia? 2. MY PERSONAL insight---My faith in a supreme God did not need bolstering, but as I am on my third time listening to this podcast, the thought that constantly runs in my mind (I don't speak for anyone but myself) is how incredible the God I believe in really is to have created humans with such intricate mechanisms. Finally, I find so many of Dr. Huberman's podcasts brilliant that I'd never be able to choose a favorite, but this one would lead the pack of competitors. Thank you, both, again.

[Car-jypw]

I like the look you get when you say your guest’s name and say welcome. Genuinely happy to start a conversation with them. Makes me happy to see them too.

[MrsEclecticTex]

Fascinating! I am an NP who manages Diabetes and have prescribed GLP-1 inhibitors for many patients (if they qualify and can negotiate the shortages in the US). Anecdotally, about 1/4 of my patients report a major benefit from “less food noise.” This description of no longer obsessing about food and feeling more in control of their eating behavior is consistently is used. The psychological benefits are real. Too bad I can’t claim CME for this interview.