Nuclear receptor 5A2 regulation of Agrp underlies olanzapine-induced hyperphagia

Abstract

Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain.

Functional coupling between MC4R and Kir7.1 contributes to clozapine-induced hyperphagia

“…Additionally, mice exhibited no preference between the two diets ( Figure S1A ), suggesting that the added clozapine did not significantly change the taste of the control diet. Previous studies have shown that the metabolic effects of APDs are substantially more potent in female mice 19,22,26 . Thus, we measured the chronic and acute effects of clozapine on energy metabolism in female C57BL/6 mice.…”

“…Given their unique binding profiles, individual APDs likely engage distinct brain circuits to alter energy metabolism. However, emerging evidence suggests that some commonly used APDs may converge on central melanocortin neurons to induce hyperphagia and weight gain 19,22 .…”

“…APDs may disturb MC4R function via different means. For example, olanzapine exposure increases the expression of the orexigenic neuropeptide AgRP, which acts via the MC4Rs 19 . Meanwhile, APDs can promote feeding by directly reducing the activity of MC4R PVH neurons.…”

“…Moreover, these findings suggest that clozapine induces function by increasing AgRP expression. Indeed, olanzapine's effect on food intake and body weight is abolished in Agrp-deficient mice 19 .…”

“…Recent studies have shown that olanzapine, an APD, boosts food intake by up-regulating Agrp transcription in the hypothalamus. Additionally, olanzapine-induced weight gain was attenuated in mice lacking Agrp 19 .…”