Chapter 13 — Exercises

Items marked † have worked solutions in Appendix M.

A. Recall

13.1 Name at least six signals feeding into the appetite network and say which tissue each comes from.

13.2 † What is leptin, what tissue produces it, and what does its level track?

13.3 What is the ob/ob mouse and what did it lead to?

13.4 What is amylin, where is it produced, and what are its three principal actions?

13.5 † Describe the melanocortin pathway: name the two neuron populations, the two ligands, and the receptor they converge on.

13.6 What is setmelanotide and what is it approved for?

13.7 Which gut hormone is orexigenic, and which is released after meals to reduce intake?

13.8 Define defended set point, redundancy, and counter-regulation as they apply here.

B. The leptin story

13.9 † Explain why the leptin model predicted a general obesity drug and why that prediction failed. Be precise about what was wrong — was it the biology, the model, or the disease?

13.10 Leptin receives ✅ for one population and ❌ for another. State both claims with their populations and explain what a source loses by omitting them.

13.11 §13.2 argues leptin's discovery was not a failure. List three things it achieved.

13.12 "Leptin resistance" names a phenomenon. Is it an explanation? What would an explanation require?

C. Amylin and architecture

13.13 † Explain the architectural difference between CagriSema and tirzepatide, and give one genuine advantage of each design.

13.14 People with type 1 diabetes are amylin-deficient as well as insulin-deficient. Using Chapter 2's override/replace rule, what does that imply about pramlintide in that population?

13.15 Amylin's actions overlap substantially with GLP-1's. Using §13.1, explain why that overlap is expected rather than surprising.

D. Melanocortins and precision

13.16 † Setmelanotide's mechanism is proven, not merely plausible. Explain why that still does not license using it in common obesity, and name the general principle.

13.17 A person with leptin receptor deficiency has high leptin and cannot respond to it. Explain why supplying more leptin fails and why an MC4R agonist can succeed.

13.18 Setmelanotide's trial population was defined by molecular diagnosis rather than phenotype. Explain why that mattered, and what it implies about drugs selected on phenotype alone.

E. Why single targets fail

13.19 † State the structural argument of §13.7 in your own words, then apply it to explain each of: leptin, PYY, ghrelin blockade.

13.20 §13.7 admits its own explanation is "partly retrospective" and does not explain the magnitude of the GLP-1 effect. Evaluate that admission — does it weaken the argument, and should the book have made it?

13.21 Why did GLP-1 receptor agonists succeed where these failed? Give at least three reasons.

F. The supplement claim

13.22 † State the four reasons "boosting" endogenous GLP-1 cannot reproduce the drug effect, and identify which requires no measurement at all.

13.23 The ❌ in §13.8 is described as attaching to "the comparison, not the ingredient." Explain why that precision matters, and what a blanket dismissal would cost.

13.24 "The hunger hormone" is called a damaging compression. Explain the damage, and name the parallel case the book flags in Chapter 21.

G. "Explain this to a friend"

13.25 † Your friend says obesity is "a hormone problem, they found the hormone in the nineties." Respond accurately and without condescension.

13.26 Explain to someone why a drug can be miraculous for a few dozen people and useless for everyone else — without making it sound like a failure.

13.27 A relative is about to buy a supplement advertised as a natural alternative to Ozempic. Respond, conceding what is true first.

H. Judgment

13.28 §13.9 predicts future combinations and explicitly declines to predict durable post-treatment change. Is that caution justified, or is the book being reflexively conservative?

13.29 † Rank leptin, PYY, ghrelin antagonism, and MC4R agonism by how much the field learned from each. Justify — and note that "learned from" and "produced a drug" are different measures.

13.30 A combination product hits four appetite targets. Using §13.1 and Chapter 8's Case Study 2, state one reason to expect greater efficacy and one to expect greater risk.

I. Evidence Dossier extension

13.31 † Complete Field 8 (Claimed use) for every peptide in your dossier, including the "gap" line and "who makes each claim."

13.32 For any dossier compound, identify a claim made by a seller or community that the manufacturer or literature does not make. That gap is epistemic laundering (Ch 6 §6.4) — record it.

13.33 Find one compound in your dossier whose marketing is narrower than its science. If there isn't one, note what that tells you about how you chose your peptides.