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Published in final edited form as: Psychoneuroendocrinology. 2024 Feb 6;163:106987. doi: 10.1016/j.psyneuen.2024.106987

Olanzapine’s effects on hypothalamic transcriptomics and kinase activity

Sandra Pereira a,b, Laura N Castellani a, Chantel Kowalchuk a, Khaled Alganem c, Xiaolu Zhang d, William G Ryan c, Raghunath Singh a, Sally Wu a,e, Emily Au a,f, Roshanak Asgariroozbehani a,e, Sri Mahavir Agarwal a,g,h, Adria Giacca b,e,h, Robert E Mccullumsmith c,i,#, Margaret K Hahn a,e,f,g,h,#
PMCID: PMC10947847  NIHMSID: NIHMS1966695  PMID: 38340539

Abstract

Olanzapine is a second-generation antipsychotic that disrupts metabolism and is associated with an increased risk of type 2 diabetes. The hypothalamus is a key region in the control of whole-body metabolic homeostasis. The objective of the current study was to determine how acute peripheral olanzapine administration affects transcription and serine/threonine kinase activity in the hypothalamus. Hypothalamus samples from rats were collected following the pancreatic euglycemic clamp, thereby allowing us to study endpoints under steady state conditions for plasma glucose and insulin. Olanzapine stimulated pathways associated with inflammation, but diminished pathways associated with the capacity to combat endoplasmic reticulum stress and G protein-coupled receptor activity. These pathways represent potential targets to reduce the incidence of type 2 diabetes in patients taking antipsychotics.

Keywords: olanzapine, RNA-seq, kinome array

1. INTRODUCTION

Antipsychotics remain the cornerstone of treatment of schizophrenia and are approved by regulatory bodies in the treatment of several other mental disorders (Baldessarini et al., 2019; Thomas, 2007). However, antipsychotic medications are associated with metabolic impairments, contributing to metabolic morbidity in a population where the leading cause of mortality remains cardiovascular disease (Ferreira et al., 2020; Pereira et al., 2023). Olanzapine (Ola) is a widely prescribed and highly efficacious second-generation antipsychotic medication that causes severe metabolic side-effects such as weight gain, disrupted glucose metabolism, and dyslipidemia (Kowalchuk et al., 2019; Pereira et al., 2023; Pillinger et al., 2020). The ability of Ola to improve psychiatric symptoms is associated with antagonism of neurotransmitter receptors in the central nervous system, including dopamine D2, serotonin 5HT2a, and serotonin 5HT2c receptors (Alvarez-Herrera et al., 2020). Ola is also an antagonist of other receptors such as muscarinic (M1 and M3) acetylcholine receptors (Alvarez-Herrera et al., 2020). Nevertheless, antagonism of at least some of these receptors in and outside of the central nervous system is also part of the mechanism through which Ola causes metabolic dysregulation (Kowalchuk et al., 2019; Lord et al., 2017).

Studies in rodents have demonstrated that acute peripheral administration of Ola causes insulin resistance in vivo under hyperinsulinemic euglycemic clamp conditions, where circulating insulin concentrations are elevated and circulating glucose is kept at fasting levels (Boyda et al., 2013; Chintoh et al., 2009; Chintoh et al., 2008; Houseknecht et al., 2007; Kowalchuk et al., 2019; Wu et al., 2014). In dogs, prolonged peripheral Ola treatment also causes insulin resistance (Ader et al., 2005). Furthermore, acute peripheral Ola administration causes insulin resistance in the brain-liver pathway of glucose metabolism regulation; this was determined by assessing the extent of endogenous glucose production (EGP) inhibition as a result of a central insulin stimulus during the pancreatic euglycemic clamp (Kowalchuk et al., 2017). The pancreatic euglycemic clamp with tracer methodology allows the investigation of glucose metabolism by the liver and other tissues under controlled (fasting) circulating concentrations of insulin and glucose. In the current study, we examined how acute peripheral Ola treatment alone affects transcription and kinase activity in the hypothalamus, which is a key regulator of whole-body metabolic homeostasis. To minimize the potential confounding effects of Ola-induced fluctuations in circulating levels of glucose and the hormones insulin and glucagon, tissue samples were collected after a pancreatic euglycemic clamp (Castellani et al., 2022). We have reported that a clinically relevant dose of peripherally administered Ola impairs central glucose sensing resulting in whole body insulin resistance during the pancreatic euglycemic clamp (Castellani et al., 2022). We now report that, under the same clamp conditions, peripherally administered Ola acutely alters various hypothalamic pathways, some of which are at the intersection of psychiatry and metabolism.

2. MATERIALS AND METHODS

2.1. Pancreatic euglycemic clamp

All methods used in the current study have already been published (Castellani et al., 2022). Briefly, experiments in animals received approval from the Centre for Addiction and Mental Health (CAMH) Animal Care Committee and followed guidelines from the Canadian Council on Animal Care. Male Sprague Dawley rats (300–400g; Charles River, Saint-Constant, QC, Canada) had free access to food and water and were kept on a 12h light/12h dark cycle. Following acclimatization, rats underwent intracerebroventricular (i.c.v.; 3rd ventricle) surgery. Rats were singly housed after this surgery until the time of euthanasia. Following ~1 week of recovery, rats underwent intravascular surgery to insert a catheter into the right jugular vein (for infusions on the day of clamp study) and a catheter into the left carotid artery (to obtain blood samples on the day of the clamp study). Rats were allowed to recover before the pancreatic euglycemic clamp was performed. On the day of the clamp study, glucose or vehicle (saline) was infused i.c.v. throughout the protocol, which lasted 3.5 h. Immediately before the start of the clamp (at 1.5 h), Ola (Toronto Research Chemicals, North York, ON, Canada) or vehicle (Veh; 1% acetic acid) was injected subcutaneously (s.c.). The Ola dose used (3mg per kg of body weight) is based on clinically relevant (>70%) D2 receptor occupancies in the brain of rats following acute dose administration (Chintoh et al., 2009; Kapur et al., 2003). During the 2-hour clamp, somatostatin was infused to block endogenous insulin and glucagon secretion, insulin was infused to maintain basal plasma insulin concentrations, and the rate of exogenous glucose infusion was altered based on periodic plasma glucose measurements to maintain euglycemia (i.e., basal plasma glucose concentrations). The pancreatic clamp protocol allows the quantification of EGP and glucose utilization using the glucose infusion rate and the specific activity resulting from the infusion of the tracer [3-3H]-glucose. At the end of the 2-hour clamp, rats were anesthetized, euthanized, and the hypothalamus was collected.

The current paper determines the effect of Ola on the hypothalamus under clamp conditions and therefore the group comparison examined is as follows (labelled in the order i.c.v.-s.c.): Veh-Ola group vs. Veh-Veh group. We have already published the hypothalamic results for i.c.v. glucose, with and without Ola, in the context of the pancreatic euglycemic clamp in relation to transcriptomics and kinomics (Castellani et al., 2022). In the previous publication, alterations in “transcriptomic and kinomic” signatures by Ola were only examined in the context of a central glucose stimulus and therefore, the group comparisons were Glucose-Veh vs. Veh-Veh and Glucose-Ola vs. Glucose-Veh. These hypothalamic changes occurred alongside blunting by Ola of i.c.v. glucose-induced in vivo glucose metabolism. In the current paper, we now report the ex vivo results of the effects of Ola alone, without the central glucose stimulus (i.e.,Ola-Veh group vs. Veh-Veh group), on hypothalamic transcriptomics and kinome array in this “clamped and euglycemic” setting, data which have not yet been published.

2.2. Ex vivo analyses

Hypothalamic samples underwent RNA sequencing (RNA-seq) and kinome array analyses, as thoroughly described previously (Castellani et al., 2022). Results are shown as a comparison of the following two experimental groups: Veh-Ola group vs. Veh-Veh group (n=4 per group, except for Veh-Veh group in RNA-seq analysis, where n=3). For RNA-seq, we report statistically significant results for full transcriptome pathway analysis and targeted pathway analysis, which occurred when p < 0.05. The former used fgsea R package (p value is calculated using multi-level split Monte Carlo approach) and the latter used enrichR R package (p value is calculated using Fisher exact test). For the kinome array, the extent of phosphorylation of immobilized peptides is indicative of serine/threonine kinase activity in hypothalamic samples. The threshold for peptides’ relative (i.e., between the two groups) signal intensities are 0.8-fold change and 1.2-fold change. Random sampling analysis was used to establish which kinases caused the alterations in peptide phosphorylation. Kinases with Z ≥ | 1.5 | (p value < 0.067) are found in the Results. Kinase acronyms refer to families that have been published elsewhere (Castellani et al., 2022).

3. RESULTS

Comparison of full transcriptome hypothalamic RNA-seq results for Ola alone (Veh-Ola vs. Veh-Veh) demonstrates that Ola: 1) stimulates pathways related to inflammation and activation of both innate and adaptive immune cells and 2) inhibits G protein-coupled receptors pathways and protein folding processes (Figure 1A). The accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER) is known as ER stress (Zhang and Kaufman, 2008). Under normal conditions, ER stress is acutely minimized by triggering a negative feedback loop known as the unfolded protein response (UPR). The UPR aims to restore normal cell function through a series of intracellular pathways; for example, by increasing the levels of chaperone proteins required for appropriate protein folding (Zhang and Kaufman, 2008). Leading edge (LE) gene analysis indicated that these pathway alterations were associated with upregulated inflammatory cytokine genes (Tnf, Il1b, Il6) and downregulated dopamine receptor genes (Drd1 and Drd2) (Figure 1B). Moreover, LE gene analysis indicated that Ola downregulated Gsk3b. Notably, GSK3B is directly inhibited by Ola (Mohammad et al., 2008).

Figure 1.

Figure 1.

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Hypothalamic RNA-seq results. (A) Top and bottom results for full transcriptome pathway analysis (gene set enrichment analysis, GSEA). (B) Leading Edge (LE) gene analysis for full transcriptome. (C) Cross-pod common pathway analysis, which refers to pathways common to full transcriptome and targeted pathway analyses. All results in this figure refer to Veh-Ola vs. Veh-Veh comparison. n=4 for Veh-Ola and n=3 for Veh-Veh.

Results from targeted Gene Ontology (GO) analysis, which focuses on the top 10% of upregulated and downregulated genes (Supplementary Figure 1), as well as GO pathways common to the full transcriptome pathway analysis and targeted pathway analysis (Figure 1C) were similar to results for the full transcriptome pathway analysis (Figure 1A). Lastly, perturbagen analysis based on cellular studies identified the top 10 discordant perturbagens that are expected to have the opposite effect of Ola on RNA-seq results (Supplementary Figure 2). Among these discordant perturbagens are Akt inhibitor IV, radicicol, and BIIB 021. These compounds have anti-inflammatory properties (Gopalakrishnan et al., 2013; Jeon et al., 2000; Wang et al., 2014) and activate the UPR (Blaustein et al., 2013; Davenport et al., 2007; Sbiera et al., 2019).

Ola also decreased hypothalamic serine/threonine kinase activity (Figure 2A). Most of these kinases were inhibited by Ola in the presence of i.c.v. glucose (i.e., Glu-Ola vs. Glu-Veh), as we previously reported (Castellani et al., 2022), but Ola alone also decreased the activity of STE7 (MAP2K1–7) and KHS (MAP4K1–3, 5) (Figure 2A). Figure 2B shows the functional consequences of Ola’s effects on kinase activity, which include decreased transcription, cation channel activity, and G protein-coupled receptor activity. The diminished G protein-coupled receptor activity is consistent with our RNA-seq results (Figure 1A and 1C). Moreover, both kinome array and RNA-seq analyses indicate that Ola decreases G protein-coupled acetylcholine receptor activity/pathways (Figure 2B and Supplementary Figure 1, respectively).

Figure 2.

Figure 2.

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Hypothalamic kinome array results. (A) Serine/threonine kinase activity; kinases are on the y-axis and refer to families. The x-axis refers to the log2 fold change in relative signal intensity of peptides targeted by kinases. The gray dots represent peptides with relative signal intensities that are below 0.8-fold change or above 1.2-fold change. (B) GO Molecular Function 2021 results based on kinome array results; length of bars reflects p-value ranking. All results in this figure refer to Veh-Ola vs. Veh-Veh comparison. n=4 for Veh-Ola and n=4 for Veh-Veh.

4. DISCUSSION

Our kinome array and RNA-seq results indicate that Ola causes inflammation and ER stress in the hypothalamus within 2 hours of administration, under steady state basal concentrations of plasma insulin and glucose (i.e., pancreatic euglycemic clamp). Moreover, the top perturbagens that are predicted to counteract the transcriptional effects of Ola are compounds that alleviate inflammation and activate pathways to combat ER stress, namely the UPR. Consistent with previous literature on the receptor binding profile of Ola (Alvarez-Herrera et al., 2020; Weston-Green et al., 2013) and its effect on G protein-coupled receptors, particularly serotonin, dopaminergic, and muscarinic receptor types (Boyd and Mailman, 2012; Kaplan et al., 1999; Millan et al., 2008; Wess et al., 2007), we found that Ola impairs G protein-coupled receptor pathways in the hypothalamus. Indeed, activation of G protein-coupled receptors using glucagon-like peptide-1 receptor (GLP-1) agonists alleviates hyperglycemia caused by Ola and reduces inflammation (Cary et al., 2023; Medak et al., 2020; Wong et al., 2023).

Multiple reports on the effects of antipsychotics on the transcriptome and proteome align with the results we describe herein. Antipsychotics increase inflammation and alter ER gene expression in the liver of patients with schizophrenia (Choi et al., 2009). The antipsychotic risperidone stimulates inflammation in peripheral blood mononuclear cells of patients with psychosis (Melbourne et al., 2020). Inflammation is augmented in the livers of mice treated with Ola or risperidone (Rostama et al., 2020). Furthermore, mice treated with risperidone show changes in proteins of the immune system in the heart (Beauchemin et al., 2020). However, analysis of the plasma proteome from schizophrenia patients treated with Ola or risperidone indicates that patients who respond well clinically to antipsychotic treatment have diminished inflammation (Garcia-Rosa et al., 2020). These findings suggest that the effect of antipsychotics on gene expression and proteins may depend on health status.

Ola is known to cause ER stress, as evidenced by the accumulation of misfolded proteins (He et al., 2019; Ninagawa et al., 2020). In our study, we found that Ola impairs hypothalamic protein folding capacity at the transcriptional level, which suggests that Ola diminishes the ability of the hypothalamus to fight ER stress. This is consistent with reports that Ola increases DNA methylation in various brain regions (Melka et al., 2014) as DNA methylation can cause a decrease in transcription (Moore et al., 2013). Indeed, we also found that Ola causes an overall decrease in hypothalamic transcriptional activity based on our kinome array results.

ER stress causes and is caused by inflammation (Zhang and Kaufman, 2008). Markers of ER stress and inflammation are present simultaneously in the hypothalamus following Ola administration (He et al., 2019). Notably, based on the RNA-seq results, we found that most of the top pathways that were stimulated by Ola were inflammatory and involved immune cell activation. Other than ER stress, another source of inflammation could be antagonism of the muscarinic acetylcholine receptors (Frinchi et al., 2019). Ola can antagonize M1 and M3 receptors (Alvarez-Herrera et al., 2020) and, based on RNA-seq and kinome array results, we found that Ola reduces G protein-coupled (i.e., muscarinic) acetylcholine receptor activity/pathways. Moreover, antagonism of dopamine D2 receptor may increase inflammation (Feng and Lu, 2021).

Despite changes in G protein-coupled receptor pathways, UPR, and inflammation, we did not observe alterations in in vivo glucose metabolism by Ola in the absence of a central stimulus (i.e., Veh-Ola vs. Veh-Veh during the clamp) (Castellani et al., 2022). This was expected based on previous findings (Kowalchuk et al., 2019; Kowalchuk et al., 2017) and it raises the question of whether reducing ER stress and/or inflammation could improve the metabolic side effects of Ola in the presence of a central stimulus such as hormones and nutrients. Hence, our results have implications for the metabolic effects of Ola throughout the feed-fast cycle. We have reported the effects of Ola on hypothalamic pathways in the context of central glucose administration (Castellani et al., 2022) and interestingly, there are similarities (e.g. inflammation) and differences (e.g. ER stress caused by Ola alone) compared to the findings reported here, where there was no central stimulus. It has been demonstrated in mice, which are nocturnal animals, that Ola or risperidone impairs body weight regulation and metabolism when administered at the beginning of the rest period (light cycle; AM) compared to near the beginning of the active period (dark cycle; PM) (Zapata et al., 2022). The beginning of the active period is associated with higher circulating concentrations of the glucoregulatory hormones GLP-1 and leptin (Zapata et al., 2022), but it is unclear if increased action by such hormones, including resolution of ER stress (Yusta et al., 2006), contributes to the improved metabolic profile in the active period upon administration of antipsychotics. Central ER stress impairs whole-body glucose metabolism (Purkayastha et al., 2011) and ER stress causes insulin as well as leptin resistance (Hosoi et al., 2008; Ozcan et al., 2004). Chemical chaperones, which resolve ER stress, prevent weight gain caused by Ola (He et al., 2019). However, it is unknown if chemical chaperones prevent Ola-induced disruptions in brain-controlled glucose metabolism by glucoregulatory hormones. Chemical chaperones such as 4-phenylbutyric acid and tauroursodeoxycholic acid are FDA approved for other disorders (Kars et al., 2010; Xiao et al., 2011), and thus our findings could have interesting implications for drug repurposing to treat or prevent metabolic adverse effects.

4.1. Conclusions

We utilized RNA-seq and kinome array analyses to determine that acute peripheral Ola treatment impairs the ability to combat ER stress, increases inflammation, and inhibits neurotransmitter-regulated G protein-coupled receptors in the hypothalamus. The ex vivo results we obtained in an acute setting may predict the effects of prolonged Ola treatment on glucose metabolism because Ola dysregulates glucose metabolism both acutely and chronically in unclamped conditions (Kowalchuk et al., 2019). In contrast, the effects of Ola on certain aspects of lipid metabolism, such as circulating free fatty acids, differ depending on treatment duration (Ballon et al., 2018; Pereira et al., 2023), which suggest distinct temporally regulated mechanisms. The findings in the current paper represent potential pathways that can be targeted to prevent Ola-induced alterations in glucose metabolism and decrease the risk of developing type 2 diabetes. Together with our previous findings (Castellani et al., 2022), the current results suggest that the effects of Ola on the hypothalamus appear to change throughout the feed-fast cycle due to alterations in circulating nutrients and hormones.

Supplementary Material

1

Highlights.

  • Use of RNA-seq and kinome array on hypothalamus samples

  • Olanzapine stimulates inflammatory pathways

  • Olanzapine inhibits pathways that combat endoplasmic reticulum stress

5. ACKNOWLEDGEMENTS

This work was supported in part by a grant awarded to M.K.H. by the Drucker Family Innovation Fund, University of Toronto. M.K.H. is supported by grants from the Banting and Best Diabetes Centre (BBDC), Canadian Institutes of Health Research (CIHR), and PSI Foundation. She is supported by an Academic Scholars Award from the Department of Psychiatry, University of Toronto, and holds the Kelly and Michael Meighen Chair in Psychosis Prevention. This work was also supported by grants awarded to R.E.M. from the National Institute of Mental Health (MH107487, MH121102) and National Institute of Health (AG057598). S.P. was awarded a postdoctoral fellowship from the Discovery Fund at CAMH. W.G.R. was supported by NIH NIGMS T32-G-RISE grant number 1T32GM144873-01.

Footnotes

7. CONFLICTS OF INTEREST

M.K.H. received consultant fees from Alkermes, Inc.

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NIHMS1966695-supplement-1.pdf (205.4KB, pdf)

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