The most quietly radical thing said all evening was not about a drug. It was Dr Federica Amati pointing out that the blockbuster everyone was asking about, GLP-1, is not some alien molecule at all. It is a hormone your own gut makes, every time you eat — and most of us, she argued, have spent years quietly switching it off.
In Part 1 we looked at the GLP-1 medicines themselves — what they do, what they cost you, and the before-during-after work that decides whether they help or harm. This part goes underneath them, to the biology Amati has just written a book about: how appetite is actually regulated, why "willpower" is the wrong word for it, and what it would take to get your own appetite hormones working again.
The End of the Willpower Story
The framing came from the moderator, Clarissa Lenherr, who noted that the whole culture is finally "moving away from this idea that weight loss and metabolism and appetite are about willpower" and toward the place the science actually points: the gut. Amati picked it up and ran. The reason she wrote her book, she said, is that "we know so much more now about how hunger is regulated" — and almost none of it is about moral fibre.
Appetite, in her telling, is an orchestra. "It's essentially an interplay between the hormones our gut produces and our brain," she explained — several different signals, all talking to each other and, specifically, to the hypothalamus, the brain's master regulator. When people feel they are "failing" at hunger, what is usually happening is that this hormonal conversation has gone quiet. That is a physiological problem, not a character one — and, crucially, a fixable one.
It's essentially an interplay between the hormones our gut produces and our brain. That is really how our appetite regulation is mastered.
Meet Your Own Appetite Hormones
Amati reeled off the cast: GLP-1, GIP, PYY, CCK, GLP-2 and GLP-3 — a handful of gut hormones, each with slightly different jobs across the gut, the pancreas and the brain, that together tell you when to stop eating and keep you feeling fed. The drugs that have reshaped the conversation simply impersonate one of them. Your gut, given the right raw materials, runs the whole ensemble itself.
The key players are the cells that make GLP-1, called L-cells. Amati's word for them is the one to remember: they are "nutrient-sensing cells." They are stimulated, as she put it, "in the presence of nutrients." When real food — fibre, healthy fats, protein — reaches them, they fire, releasing GLP-1 and PYY, which travel to the hypothalamus and register as satisfied. No food arriving where the L-cells live, no signal. It is, mechanically, that simple.
Why Your Appetite Hormones Fell Asleep
Here is the part that reframed how I think about my own meals. The L-cells are concentrated toward the far end of the gut — the distal colon. For them to fire, nutrients actually have to reach them. And the modern way of eating is almost perfectly designed to make sure nothing ever does.
"If we don't eat any fibre, if we don't have any healthy fats — from nuts, for example," Amati said, "by the time anything reaches our distal colon, there are no nutrients to stimulate our L-cells, and they're asleep." High-energy drinks and ultra-processed foods make it worse: they are "mostly absorbed high up" in the gut, all their calories stripped out long before they get anywhere near the sensors. You take in the energy. You never send the signal.
By the time anything reaches our distal colon, there are no nutrients to stimulate our L-cells, and they're asleep. And so then we wonder why we feel hungry.
That single line undoes a lot of self-blame. The person who eats a "healthy" breakfast smoothie and is starving by eleven is not weak-willed; they have eaten something absorbed so high up that their L-cells never woke. The hunger that follows is the predictable output of a system that was never switched on. Fix the input — get real nutrients all the way down — and the body starts making its own satiety signal again.
Full, or Satiated?
Amati draws a sharp line between two states we tend to lump together. Fullness is mechanical — the stretch of a loaded stomach, and it fades fast. Satiety is hormonal — the GLP-1 and PYY signal that says you are nourished, you can stop, and it lasts. The goal, she said, is to "feel really satiated, not just full for half an hour." Rose Ferguson made the practical corollary: protein matters here partly because it takes longer to digest and triggers its own satiety signals, which is exactly why it is the first thing appetite-suppressed people stop eating enough of.
Nourishing ourselves properly can help us thrive with the foods we eat and actually feel really satiated — not just full for half an hour.
The empowering corollary is the one Amati left hanging at the end of the GLP-1 discussion in Part 1: do this well enough and some people "may not take the drugs — they might find their endogenous signalling is enough." You cannot promise that for everyone, and for many with obesity or diabetes the medicines are genuinely needed. But the principle holds for all of us: the appetite system is built to work, and it responds to what you feed it.
- 1Feed the far end. Fermentable fibre — whole grains, legumes, vegetables, nuts — is what survives digestion to reach the L-cells in the distal gut. This is the single biggest lever, and it is where Part 3 of this series goes next.
- 2Add protein and healthy fats. Both trigger satiety signals (CCK among them) and slow stomach emptying. Protein in particular keeps you satisfied for longer — prioritise it.
- 3Eat food, not liquid calories. Smoothies, energy drinks and ultra-processed foods are absorbed high up and never reach the sensors. Whole, structured food does.
- 4Give the signal time to arrive. Satiety hormones take roughly twenty minutes to register. Eating slowly lets them — the subject of Part 4.
The drug borrows the body's language.
You can speak it for free.
The reason this was the most important ten minutes of the night is that it dissolves the central myth of dieting. Appetite is not a test of willpower; it is a hormonal conversation between your gut and your brain — one you have probably muted with low-fibre, ultra-processed, high-up-absorbed food. The GLP-1 medicines work by shouting that conversation back to life from the outside. Real food works by switching it back on from the inside.
That is the whole foundation the rest of this series builds on. Next, the single biggest lever for waking those nutrient-sensing cells, and the most robust finding in all of gut science: diversity, not deprivation.
- 01Gribble FM, Reimann F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nature Reviews Endocrinology. 2019;15(4):226-237.
- 02Chambers ES, Viardot A, Psichas A, et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity. Gut. 2015;64(11):1744-1754.
- 03Batterham RL, Cowley MA, Small CJ, et al. Gut hormone PYY3-36 physiologically inhibits food intake. Nature. 2002;418(6898):650-654.
- 04Tolhurst G, Heffron H, Lam YS, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2012;61(2):364-371.
- 05Rehfeld JF. Cholecystokinin — from local gut hormone to ubiquitous messenger. Frontiers in Endocrinology. 2017;8:47.
- 06Quotations are drawn from the gut-health panel at Healf's HX26 conference, with Dr Federica Amati and Rose Ferguson, moderated by Clarissa Lenherr, London, June 2026. Attributions reflect the views the speakers expressed at that event; physiological mechanisms are sourced independently to the literature above.