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Weight loss at a cost: Semaglutide and PYY3-36 aggravate pre-existing metabolic osteoporosis in female rats

ABSTRACT: Incretin mimetics like semaglutide and peptide YY3-36 (PYY3-36) reduce appetite and body weight, however their individual and combined effects on bone health in the setting of metabolic disease and associated osteoporosis (MetOP) lack mechanistic insights. Here, a recently introduced MetOP rat model using Western diet and nitric oxide synthase inhibitor L-NAME is used to study effects of semaglutide, PYY3-36 and their combination on bone health. Semaglutide modestly imapired bone health by increased bone resorption, confirmed by microCT and histological analysis, RNA-Sequencing revealed a downregulation of cell cycle and osteoblast related genes. PYY3-36 treatment led to deteriorated bone markers and increased resorption, potentially limiting its clinical application, while angiogenesis and extracellular matrix-associated genes showed an upregulation in RNA-Seq based pathway analysis. Semaglutide and PYY3-36 in combination further aggravated bone loss in MetOP. These findings highlight the need to evaluate gut hormone–based weight loss strategies for long-term skeletal safety, especially in the vulnerable setting of pre-existing osteoporosis.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE320176 | GEO | 2026/04/01

REPOSITORIES: GEO

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Weight loss at a cost: Semaglutide and PYY3-36 aggravate pre-existing metabolic osteoporosis in female rats

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