Physiology of Appetite Regulation

1. Central Command: The Hypothalamus

• Lateral Hypothalamic Area (LHA) - the "hunger (feeding) center." Stimulation drives eating; destruction causes anorexia.
• Ventromedial/Ventral Posterior Nucleus (VMN/VPN) - the "satiety center." Stimulation inhibits eating; lesions cause hyperphagia and obesity.

• Costanzo Physiology 7th Ed., p. 352

2. The Arcuate Nucleus: Two Opposing Neuronal Populations

• Medical Physiology (Boron & Boulpaep), pp. 1472-1473

3. Secondary Neuron Projections

1. Lateral Hypothalamic Area (LHA) - NPY/AgRP neurons stimulate secondary neurons that release the orexigenic peptides melanin-concentrating hormone (MCH) and orexins A and B (hypocretins). POMC neurons inhibit these.
2. Ventromedial Hypothalamic Nucleus (VMN) - satiety center.
3. Dorsomedial Hypothalamic Nucleus (DMN).
4. Paraventricular Nucleus (PVN) - projects to the cerebral cortex and brainstem; α-MSH activates MC4R here to generate satiety signals.
5. Periventricular nucleus - receives GLP-1 input.

• Medical Physiology (Boron & Boulpaep)

4. Peripheral Signals - Long-Term (Adipostatic) Regulators

Leptin

• Source: Adipocytes, in proportion to fat mass
• Action: Crosses the blood-brain barrier → stimulates arcuate POMC/CART neurons AND suppresses NPY/AgRP neurons → decreases appetite + increases energy expenditure
• Time course: Intermediate- to long-term regulator (half-life ~75 min; not acutely affected by single meals)
• Receptor: LEP-R (tyrosine kinase-associated, signals via JAK2/STAT), richly expressed in arcuate nucleus
• Leptin-deficient Ob/Ob mice gain >100% body weight; parabiosis experiments were the key evidence for a blood-borne satiety factor (see classic parabiosis figure below)
• Most obese humans are not leptin-deficient but are leptin resistant (plasma levels actually rise with BMI)

Insulin

• Source: Pancreatic β cells; fluctuates throughout the day with meals
• Action: Same as leptin - stimulates POMC neurons, suppresses NPY/AgRP neurons → decreases appetite
• Time course: Short- to intermediate-term regulator (levels change acutely with each meal)
• Costanzo Physiology 7th Ed., p. 352 | Medical Physiology, p. 1471

5. Peripheral Signals - Short-Term (Meal-by-Meal) Regulators

Ghrelin (the hunger hormone)

• Source: Gastric mucosal cells, secreted just before meals (rises during fasting)
• Action: Activates NPY/AgRP neurons and inhibits POMC neurons → increases appetite and food intake
• Unique feature: The only known circulating orexigenic (appetite-stimulating) hormone
• Ghrelin opposes leptin; starvation and weight loss strongly stimulate ghrelin secretion

Cholecystokinin (CCK)

• Source: I cells of the duodenum and jejunum, released in response to protein and fat
• Action: Binds CCK-1 receptors on vagal afferents → signals to the brainstem → promotes meal termination (satiation). Also delays gastric emptying.
• Proof of physiologic role: CCK receptor antagonists increase meal size
• Note: CCK causes satiation (stops the current meal) but does not affect satiety (duration until next meal)

GLP-1 (Glucagon-like Peptide-1)

• Source: L cells of the ileum and colon, released in response to luminal nutrients
• Action: Stimulates insulin secretion (incretin effect) + delays gastric emptying + inhibits appetite. GLP-1 receptors are found in the arcuate nucleus, PVN, and dorsomedial hypothalamus.
• Central administration of GLP-1 also suppresses food intake.
• Basis for GLP-1 receptor agonists (semaglutide, liraglutide) as anti-obesity treatments.

Peptide YY (PYY 3-36)

• Source: L cells of the ileum and colon, secreted after meals (in proportion to caloric intake)
• Action: Acts on Y2 receptors in the arcuate nucleus to decrease hunger. Also inhibits ghrelin secretion. Signals that digestion is complete.

Amylin

• Source: Pancreatic β cells (co-secreted with insulin)
• Action: Acts on the GI tract and hypothalamus to inhibit appetite. Its analog pramlintide is used clinically.

Summary table of GI satiety/hunger signals:

• Sleisenger & Fordtran's GI and Liver Disease | Costanzo Physiology 7th Ed. | Goldman-Cecil Medicine

6. Brain Regions Beyond the Hypothalamus

• Goldman-Cecil Medicine, p. 2371

7. Key Integrating Concept: Hunger vs. Satiety Balance

• Energy deficit (low leptin, low insulin, high ghrelin) → NPY/AgRP neurons dominate → hunger, increased food intake, decreased energy expenditure
• Energy surplus (high leptin, high insulin, high PYY/GLP-1) → POMC/CART neurons dominate → satiety, decreased food intake, increased energy expenditure via sympathetic activation

8. Clinical Relevance

• Leptin resistance is present in the majority of obese individuals (plasma leptin is elevated but ineffective)
• MC4R mutations account for the most common form of monogenic human obesity (~4% of severe early-onset cases)
• Bariatric surgery markedly lowers ghrelin and raises PYY/GLP-1 - contributing to its appetite-suppressing effects beyond mere restriction
• GLP-1 receptor agonists (semaglutide, liraglutide) exploit the central anorexigenic GLP-1 pathway for obesity treatment
• Orexin (hypocretin) deficiency in the LHA causes narcolepsy - illustrating the overlap between appetite regulation and sleep/wake circuits

• Costanzo Physiology, 7th Ed., pp. 350-353
• Medical Physiology (Boron & Boulpaep), pp. 1471-1474
• Goldman-Cecil Medicine, p. 2371
• Sleisenger & Fordtran's GI and Liver Disease, pp. 1937-1950
• Principles of Neural Science (Kandel), 6th Ed.

Pharmacotherapy of Obesity

Overview: FDA-Approved Agents for Long-Term Use

1. Orlistat (Xenical; OTC: Alli)

• Only peripherally acting agent (minimal systemic absorption <1%)
• Approved for children ≥12 years
• FDA-approved for OTC use (2007)
• No cardiovascular or CNS effects
• Harrison's Principles of Internal Medicine 22E, p. 3236 | Miller's Anesthesia 10e

2. Phentermine / Topiramate ER (Qsymia)

• Phentermine (Schedule IV): Releases norepinephrine and dopamine and inhibits their reuptake in the CNS → suppresses appetite and increases resting metabolic rate. Most commonly prescribed single antiobesity drug in the USA.
• Topiramate ER: Anticonvulsant; independently causes weight loss (mechanism not fully established - likely includes glutamate receptor modulation and carbonic anhydrase inhibition). Added to counteract phentermine's stimulant effects (sedation from topiramate balanced by phentermine).

• Pregnancy (topiramate causes cleft palate and other birth defects) - pregnancy test required before starting; use effective contraception
• Glaucoma, hyperthyroidism, MAOIs within 14 days
• Uncontrolled hypertension (phentermine component)
• Harrison's 22E | Lippincott Pharmacology, p. 756

3. Naltrexone / Bupropion SR (Contrave)

• Bupropion stimulates hypothalamic POMC neurons (anorexigenic) → triggers α-MSH release → satiety. Bupropion also inhibits dopamine/NE reuptake.
• Naltrexone blocks the autoinhibitory opioid feedback that POMC neurons exert on themselves - normally, β-endorphin (a POMC product) feeds back to inhibit POMC activity. Naltrexone removes this brake, amplifying bupropion's effect on POMC neurons. Together, they curb food cravings and reward-driven eating.

• Seizure disorders or any condition predisposing to seizures (bupropion lowers seizure threshold)
• Uncontrolled hypertension
• Chronic opioid use (naltrexone will precipitate withdrawal)
• MAOIs within 14 days
• Pregnancy
• Harrison's 22E | Lippincott Pharmacology

4. Liraglutide 3.0 mg (Saxenda)

5. Semaglutide 2.4 mg (Wegovy) - "Second-Generation"

• STEP 1-4: 6.2-14.8% placebo-subtracted at 68 weeks
• STEP 5: 12.6% at 104 weeks
• STEP TEENS: 16.1% BMI reduction in adolescents vs. +0.6% for placebo

• Harrison's 22E, p. 3236-3237 | Sabiston Surgery

6. Tirzepatide (Zepbound) - "Third-Generation" Dual Agonist

• SURMOUNT-1: ~20.9% total body weight loss at 15 mg (vs. 3.1% placebo) at 72 weeks
• SURMOUNT-3: ~24.3% total body weight loss at 15 mg
• Placebo-subtracted weight loss ranged from 11.6% to 21.4% across SURMOUNT 1-4 trials

• Harrison's 22E, p. 3237 | Robbins Pathology | Sabiston Surgery

7. Setmelanotide (Imcivree)

• POMC deficiency
• Proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency
• Leptin receptor (LEPR) deficiency

• Harrison's 22E | Miller's Anesthesia 10e

8. Short-Term Agents (Not for Chronic Use)

9. Treatment Algorithm and Current Guidelines

• BMI ≥30 kg/m², OR
• BMI ≥27 kg/m² + at least one weight-related comorbidity

• All pharmacotherapy should accompany lifestyle intervention (not replace it)
• If <5% weight loss at 12 weeks on maximum tolerated dose → reassess, consider switching
• These drugs generally require long-term or indefinite use - weight regain is the norm on discontinuation
• GLP-1 RA/tirzepatide: hold 1-2 weeks before elective surgery (delayed gastric emptying → aspiration risk)

10. Drugs Withdrawn from Market

• Lorcaserin (serotonin 2C agonist) - withdrawn 2020 due to increased cancer risk
• Sibutramine (SNRI) - withdrawn 2010 due to increased CV events (SCOUT trial)
• Rimonabant (CB1 antagonist) - never approved in USA; withdrawn in Europe 2008 due to severe psychiatric adverse effects (depression, suicidality)

Summary: Mechanism-Based Classification

PERIPHERAL ACTION
  └── Orlistat (lipase inhibitor - GI only)

CENTRAL/HYPOTHALAMIC
  ├── Phentermine, diethylpropion (NE/DA release - short-term)
  ├── Naltrexone/bupropion (POMC pathway + mesolimbic reward)
  └── Setmelanotide (MC4R agonist - genetic obesity)

INCRETIN-BASED (GI + CNS)
  ├── Liraglutide 3.0 mg (GLP-1 RA - daily SC)
  ├── Semaglutide 2.4 mg (GLP-1 RA - weekly SC) ← CV outcomes benefit
  └── Tirzepatide 15 mg (dual GLP-1/GIP RA - weekly SC) ← greatest weight loss

COMBINATION (CNS)
  └── Phentermine/topiramate ER (adrenergic + anticonvulsant)

• Harrison's Principles of Internal Medicine 22E (2025), Ch. 414
• Lippincott Illustrated Reviews: Pharmacology, Ch. 22
• Miller's Anesthesia 10e, Ch. on Pharmacotherapy for Weight Loss
• Sabiston Textbook of Surgery (Glucagon-Like Peptide-1 Receptor Agonists)
• EASO Framework for Pharmacological Treatment of Obesity, Oct 2025
• Canadian Clinical Practice Guideline 2025
• PMID 40952752 (GLP-1 RA in pediatric obesity, 2025 meta-analysis)