A patient on semaglutide (GLP-1 receptor agonist) reports significant nausea and a 4 kg weight loss over 3 months. The weight loss mechanism of GLP-1 receptor agonists primarily involves:
- A Activation of hypothalamic POMC/CART neurons and inhibition of NPY/AgRP neurons, reducing food intake; and delayed gastric emptying ✓
- B Suppression of ghrelin secretion from the gastric fundus
- C Activation of brown adipose tissue thermogenesis via beta-3 adrenoceptors
- D Inhibition of pancreatic lipase activity reducing dietary fat absorption
Explanation
GLP-1 receptors are expressed in hypothalamic arcuate nucleus neurons. Agonism activates anorexigenic POMC/CART neurons (pro-opiomelanocortin and cocaine-and-amphetamine-regulated transcript) while inhibiting orexigenic NPY/AgRP neurons, reducing appetite and caloric intake. GLP-1 receptor agonists also directly reduce gastric motility (delayed gastric emptying), contributing to early satiety and nausea. The peripheral and central mechanisms together account for the substantial weight reduction seen with semaglutide (average 15% with weekly 2.4 mg dose). Ghrelin suppression is minimal; brown fat activation and lipase inhibition are not significant mechanisms.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.