GLP-1 receptor agonists (e.g., semaglutide) produce weight loss through which central mechanism?

• A Activation of hypothalamic NPY/AgRP neurons causing decreased appetite
• B Blockade of the reward dopaminergic pathway in the nucleus accumbens
• C Activation of POMC/CART neurons in the arcuate nucleus and inhibition of hypothalamic orexigenic pathways, promoting satiety ✓
• D Inhibition of ghrelin release from fundic cells

Explanation

GLP-1 receptors are expressed on POMC/CART (anorexigenic) neurons in the hypothalamic arcuate nucleus and on NPY/AgRP (orexigenic) neurons where GLP-1 agonism is inhibitory. GLP-1 receptor activation enhances POMC/CART signalling, promoting satiety and reducing caloric intake; it also signals via the dorsal vagal complex and nucleus tractus solitarius. Ghrelin inhibition is an additional peripheral contribution, but the primary central appetite suppression is via POMC/CART activation. NPY/AgRP activation would increase appetite. The dopaminergic reward pathway is not the primary mechanism.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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