Dr. Zachary Knight: Professor of physiology at UC San Francisco and a Howard Hughes Medical Institute investigator whose lab studies homeostasis, mapping the brain circuits that drive hunger, thirst and body-temperature regulation.
What this episode covers
Andrew Huberman and Dr. Zachary Knight take a deep dive into the modern neuroscience of appetite. They cover the brain's two-system control of eating (a short-term brain-stem 'meal size' system and a long-term hypothalamic 'body fat' system), the discovery of leptin, and surprising findings from Knight's lab that hunger (AgRP) neurons predict how much you'll eat before you take a bite. The conversation then turns to the science and history of GLP-1 drugs (Ozempic, Mounjaro and beyond), explaining how they were discovered, why they work, their unexpected health benefits, and the next generation of dual- and triple-agonist obesity drugs. They also explore dopamine's true role in eating (wanting vs. liking, learning rather than pleasure), the genetics of obesity, ultra-processed foods, and the tightly regulated systems controlling thirst and salt appetite.
Also referenced (named, not recommended)
Ozempic (semaglutide)
Novo Nordisk
“then semaglutide came along um and that that was approved for diabetes in 2017 and semaglutide is OIC or also marketed as wig oie”— Zachary Knight
Wegovy (semaglutide)
Novo Nordisk
“semaglutide is OIC or also Al also uh marketed as uh wig oie for weight loss and semaglutide now has a half life of seven days”— Zachary Knight
Mounjaro (tirzepatide)
Eli Lilly
“tepati which is know as mojarro for diabetes and zap Bound for obesity which is even better really in almost every respect a better drug than than OIC”— Zachary Knight
Zepbound (tirzepatide)
Eli Lilly
“tepati which is know as mojarro for diabetes and zap Bound for obesity which is even better really in almost every respect a better drug”— Zachary Knight
Liraglutide (Saxenda / Victoza)
Novo Nordisk
“I think the next big Advance was this Compound L glutide um and L glutide was approv for diabetes in 2010 and for and then for weight loss in 2014”— Zachary Knight
Exenatide (Byetta)
AstraZeneca
“the first glp1 drug that was approved was just this molecule from this lizard basically it's called exenatide and it's approved in 2005”— Zachary Knight
Januvia (sitagliptin, DPP-4 inhibitor)
Merck
“those are improved diabetes drugs they're called gpon you've probably heard about them Genovia is the most common one”— Zachary Knight
Setmelanotide (Imcivree)
Rhythm Pharmaceuticals
“there is one drug that's now approved it's called I think I'm going to get the name wrong it's like set MTI or something like this it's an mc4 receptor Agonist”— Zachary Knight
AMG 133 (maridebart cafraglutide)
Amgen
“there's this compound from Amgen it's called just right now it's just a code it's like AMG 133”— Zachary Knight
Big reveals from this episode
- Knight's lab found AgRP hunger neurons shut off within seconds of seeing food, before the first bite, predicting how much the animal will eat.
- Amgen/Amgen-era leptin was hyped to 'cure obesity' but failed in obese people because they are leptin-resistant, not leptin-deficient.
- Body weight is ~80% heritable, one of the most heritable traits known, second only to height.
- DPP-4 inhibitors raise natural GLP-1 threefold yet cause no weight loss, proving GLP-1's natural job isn't body-weight control.
- Ozempic's cardiac benefits appeared before patients lost weight, hinting at anti-inflammatory effects independent of weight loss.
- Eli Lilly's triple-agonist (GLP-1 + GIP + glucagon) drove ~25% weight loss in a phase 2 trial and people were still losing, approaching bariatric-surgery territory.
- Stimulating thirst neurons is deeply aversive (mice work hard to stop it), while hunger neurons mainly make food more attractive rather than feeling unpleasant.
- Old dogma said only the long-term hypothalamic system could change body weight; GLP-1 drugs disproved it by hammering the short-term brain-stem system 24/7.
Worth remembering
- A 'decerebrate' rat with 80% of its brain removed can still regulate the size of a single meal using only its brain stem.
- Leptin, cloned in 1994, is secreted by fat in direct proportion to body-fat reserves, giving the brain a readout of energy stores.
- To AgRP neurons, 120 calories of olive oil and 120 calories of chicken are equally satiating, they track calories, not macronutrients.
- For every ~2 lbs of weight lost, energy expenditure drops ~30 calories/day and hunger rises ~100 calories/day, explaining why weight is regained.
- GLP-1 has a natural half-life of just ~2 minutes; engineering pushed it from 2 min to 2 hrs to 13 hrs to 7 days (semaglutide).
- The first GLP-1 drug, exenatide, came from the venom of the Gila monster, a lizard with long gaps between meals.
- Ozempic-class drugs raise GLP-1 a thousand- to ten-thousand-fold, levels no food or supplement can ever replicate.
- In New Zealand studies, wild rabbits drink zero water nine months a year, getting all their hydration from food.
- The brain detects a mere 1% rise in blood osmolality as thirst; a 20% rise can land you in the hospital.
- Water leaves the stomach almost instantly, but high-fat, high-calorie food can take hours, regulated by gut feedback on gastric emptying.