Female rats given olanzapine for 24 weeks gained more weight than rats given a vehicle solution, with the difference becoming statistically significant from week 18. By the end of treatment, the olanzapine group’s average body weight was more than 10% higher than the control group’s. The result comes from an animal study of molecular changes in the dorsal raphe nucleus, or DRN, a brain region the researchers examined for clues about treatment-associated weight gain.
The study does not establish a mechanism connecting the DRN changes with weight gain. It reports a rat comparison of body weight, DRN proteins and biochemical markers, but no functional pathway-validation experiment.
What the researchers measured
The researchers randomly divided 36 female Sprague-Dawley rats into an olanzapine group and a vehicle-control group. The treatment was delivered in drinking water at 2.4 mg per kilogram of body weight per day for 24 continuous weeks. Controls received drinking water containing 0.5% sodium carboxymethyl cellulose. The methods report a 96% power calculation, a two-week acclimatization period and body-weight-based serpentine sorting before group assignment.
For the protein analysis, six DRN tissue samples were randomly selected for mass spectrometry. The researchers classified proteins as differentially expressed when the Benjamini-Hochberg-adjusted p-value was below 0.05 and the reported expression ratio was above 1.2 or below 0.833. Each sample was analyzed twice as a technical replicate, and data with a coefficient of variation below 15% were included.
The study used Student’s t-test, Welch’s t-test when variances were unequal and the Mann-Whitney U test for non-normal data. Weight measured over time was assessed with repeated-measures analysis of variance and Sidak-adjusted follow-up tests, with p below 0.05 treated as statistically significant.
Protein changes pointed to synaptic and calcium pathways
The DRN proteomics analysis identified 193 proteins that differed between the groups: 156 were higher in the olanzapine group and 37 were lower. Pathway analysis grouped these changes into 35 organismal-system pathways, including 24 top pathways reported at p below 0.01. It also identified 12 environmental-information pathways, with calcium signaling ranked as the top pathway at p below 0.001.
A protein-protein interaction, or PPI, analysis linked selected proteins to neurotransmitter synthesis or metabolism and synaptic signal transmission. The network included Ddc, Tph2, Gad1 and Gchfr in the first group, and Grm1, Gabra2, Gabra4, Chrnb2, Gng3, Gng13, Gnb4 and Slc17a7 in the second. It did not establish functional interactions or mediation.
The researchers selected seven proteins for a second round of testing because they were associated with serotonergic, glutamatergic or GABAergic synapses, or appeared as PPI hub nodes. Selection required a fold change of at least 1.5 or at most 0.67, together with p below 0.05. The team then used qPCR and Western blotting to validate the candidates at the RNA and protein levels.
In the treated rats, Tph2 and Mtor mRNA were lower, while Cacna1c, Map3k5, Prkcb, Ryr3 and ITPR1 mRNA were higher. Western blotting confirmed protein levels for all seven targets. The study did not perform functional pathway-validation experiments, so the expression results alone do not show what role the targets played in the weight difference.
Inflammation and oxidative stress were also higher
The olanzapine-treated rats had higher levels of the inflammatory marker IL-1β and the oxidative-stress measures malondialdehyde, or MDA, and reactive oxygen species, or ROS, in the DRN than controls. The reported comparisons were p = 0.0022 for IL-1β, p = 0.03 for MDA and p = 0.0014 for ROS.
The study did not collect a comprehensive metabolic profile. Body weight was the reported metabolic phenotype, without measures of food intake, body composition, insulin sensitivity, glucose tolerance, lipid profiles or energy expenditure.
Evidence remains limited to one rat model
The study involved only female rats, and its proteomics work was restricted to the DRN. The validation phase had a relatively small sample, and no experiment directly tested whether the altered pathways mediated weight gain.
These limits leave open whether the same molecular pattern would appear in male rats, in other brain regions or under different metabolic conditions. The study therefore provides a molecular association within this rat model, not a demonstrated explanation for olanzapine-associated weight gain.
The animal work received Ethics Committee approval No. 2021–2 and was conducted under the stated Chinese laboratory-animal regulations. The study was funded by the National Natural Science Foundation of China through grant 82360920.
Paper data and sources
Original title: Regulation on the metabolic synaptic pathway in the dorsal raphe nucleus in a rat model chronic olanzapine-induced body weight gain
Authors: Huang P, Zhu J, Xia Z et al.
Journal/Repository: Frontiers in pharmacology
Status: Peer-reviewed
First online: 2026-10-08
DOI: Not available
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