Effects of olanzapine on glucose metabolism in Negr1-deficient mice: sex-specific differences

Introduction

Second-generation antipsychotics, including olanzapine, are widely used in the treatment of psychiatric disorders but are associated with metabolic side effects such as hyperglycaemia and weight gain, contributing to increased cardiometabolic risk. These effects can occur independently of changes in energy balance, suggesting direct pharmacometabolic mechanisms. Substantial inter-individual variability indicates a role for genetic factors. The neuronal growth regulator 1 (NEGR1) gene has been implicated in both psychiatric disorders and metabolic regulation in genome-wide association studies (GWAS), and its deficiency has been linked to prediabetic phenotypes and altered lipid metabolism in mice. We therefore hypothesised that NEGR1 modulates susceptibility to olanzapine-induced metabolic effects.

Aims

To determine whether NEGR1 deficiency alters the metabolic response to olanzapine, focusing on glucose regulation and body weight, and to assess sex-specific effects.

Methods

A total of 113 mice (59 males, 54 females), including Negr1-deficient (KO) and wild-type controls (WT), were studied. Animals were randomised into control and olanzapine-treated groups based on baseline body weight and glucose tolerance (area under the curve, AUC, from glucose tolerance tests, GTT). Baseline assessments were conducted approximately 6 weeks before the treatment. Mice were then exposed to an olanzapine-containing diet (5 mg/kg) for 6 weeks, during which body weight was monitored. GTT was repeated post-intervention. Baseline differences were analysed using independent samples T-tests. Treatment effects were assessed using two-way ANOVA (genotype × treatment), followed by Šidák post hoc tests. Time-point-specific effects were evaluated using independent samples t-tests.

Results

Baseline glucose tolerance (AUC) did not differ between genotypes in either sex (males: p = 0.922; females: p = 0.607). Contrary to our hypothesis, olanzapine did not affect overall glucose tolerance, as reflected by unchanged AUC across groups following treatment (all p > 0.7). No significant post-treatment differences were observed between saline and olanzapine-treated groups. However, time-resolved analyses revealed a genotype- and sex-specific effect. Male Negr1-deficient mice showed reduced glucose levels at 30 minutes during GTT after olanzapine treatment compared to WT (approximately 14–15 vs 16–17 mmol/L, p = 0.02), indicating altered early-phase glucose handling. This effect was not observed in females, where only a non-significant trend was detected (p = 0.06). No consistent genotype differences were observed at other time points. Negr1-deficient males also displayed lower baseline body weight compared with WT (p = 0.005), while, contrary to our hypothesis, olanzapine did not induce significant weight gain in either sex. These findings suggest a selective, temporally restricted metabolic phenotype associated with NEGR1 deficiency.

Conclusions

NEGR1 deficiency may selectively modulate early-phase glucose handling in response to olanzapine in a sex-specific manner, despite the absence of global metabolic disruption. These findings support a potential role for NEGR1 in inter-individual variability in metabolic responses to antipsychotic treatment and highlight the importance of time-resolved and sex-stratified analyses. This may inform individual metabolic risk during antipsychotic treatment.

References

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