Discussion Guide — Chapter 13

1. "Two mice, joined at the circulation. One loses weight, the other's healthy partner starves. What do you conclude?"

Open with the parabiosis experiments before naming leptin. Listen for: students inferring a circulating factor, then — the harder step — inferring that the second mouse produces it in excess and cannot respond. When someone gets there, point out they have just reconstructed the resistance phenomenon that the field then spent a decade under-weighting.

2. "Was the leptin decade a failure?"

Listen for: the split between "no drug" and "enormous knowledge." Then push: which measure should govern funding? Students who argue for the second have to explain how you would distinguish it in advance from a line of research that produces neither, which is genuinely hard and worth sitting with.

3. "Setmelanotide's mechanism is proven, not just plausible. So why doesn't it work for common obesity?"

The chapter's hardest question. Listen for: the conditional — the demonstration was of MC4R agonism correcting a deficient signal. Watch for students who try to answer with "it's a different disease," which is true and doesn't explain anything until they say what differs.

4. "A drug for a few dozen people, at a very high price. Defend it. Then attack it."

Listen for: the orphan-incentive argument on one side and the health-system-budget argument on the other, and — ideally — someone noticing that both are correct simultaneously. The structural observation worth reaching: the smaller the population, the stronger the case for public development and the weaker the constituency to demand it.

5. "Is the supplement claim nonsense?"

Listen for: students who say yes immediately. Then give them the true part — fermentable fiber does raise postprandial GLP-1 — and ask them to rebut it. The lesson is Chapter 6 §6.5's: a dismissal that ignores the true part loses to anyone who knows the physiology, and the precise ❌ is what survives contact.

6. "Four times now: total deficiency, exact replacement, dramatic response. What does that pattern predict?"

Close here. Leptin, setmelanotide, mecasermin, insulin. Listen for: the prediction that the next genuinely dramatic peptide treatment will come from a molecularly defined deficiency rather than from optimizing a working system — and then for someone noticing that Part III is entirely about compounds given to people with no established deficiency at all. That is the transition into the next six chapters, and having the class articulate it is better than announcing it.