Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Feb 11;25(4):2188.
doi: 10.3390/ijms25042188.

Sex-Specific Effects of Long-Term Antipsychotic Drug Treatment on Adipocyte Tissue and the Crosstalk to Liver and Brain in Rats

Karin Fehsel  1 , Marie-Luise Bouvier  1
Affiliations

Sex-Specific Effects of Long-Term Antipsychotic Drug Treatment on Adipocyte Tissue and the Crosstalk to Liver and Brain in Rats

Karin Fehsel et al. Int J Mol Sci. .

Abstract

Antipsychotic drug (APD) medication can lead to metabolic dysfunctions and weight gain, which together increase morbidity and mortality. Metabolically active visceral adipose tissue (VAT) in particular plays a crucial role in the etiopathology of these metabolic dysregulations. Here, we studied the effect of 12 weeks of drug medication by daily oral feeding of clozapine and haloperidol on the perirenal fat tissue as part of VAT of male and female Sprague Dawley rats in the context of complex former investigations on brain, liver, and blood. Adipocyte area values were determined, as well as triglycerides, non-esterified fatty acids (NEFAs), glucose, glycogen, lactate, malondialdehyde equivalents, ferric iron and protein levels of Perilipin-A, hormone-sensitive-lipase (HSL), hepcidin, glucose transporter-4 (Glut-4) and insulin receptor-ß (IR-ß). We found increased adipocyte mass in males, with slightly higher adipocyte area values in both males and females under clozapine treatment. Triglycerides, NEFAs, glucose and oxidative stress in the medicated groups were unchanged or slightly decreased. In contrast to controls and haloperidol-medicated rats, perirenal adipocyte mass and serum leptin levels were not correlated under clozapine. Protein expressions of perilipin-A, Glut-4 and HSL were decreased under clozapine treatment. IR-ß expression changed sex-specifically in the clozapine-medicated groups associated with higher hepcidin levels in the perirenal adipose tissue of clozapine-treated females. Taken together, clozapine and haloperidol had a smaller effect than expected on perirenal adipose tissue. The perirenal adipose tissue shows only weak changes in lipid and glucose metabolism. The main changes can be seen in the proteins examined, and probably in their effect on liver metabolism.

Keywords: clozapine; glucose; glucose transporter-4; haloperidol; insulin receptor-ß; lipid; perilipin-A hormone-sensitive lipase; perirenal adipose tissue.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Significant increase of percental weight gain between male controls and clozapine-treated Sprague Dawley rats with p = 0.022 and n = 10 animals per group (m = male, f = female, Contr = Control, Halo = haloperidol-medicated, Cloz = clozapine-medicated). * p ≤ 0.05.
Figure 2
Figure 2
Exemplary presentation of 20 µm frozen fat sections of male and female Sprague Dawley rats after 12-week medication with haloperidol or clozapine, stained with Mayer’s hematoxylin. Two hundred adipocytes from each of two slices were counted (marked by X), their area was calculated with Axiovision (Zeiss, Germany) and the values were averaged. Values are given in Table 1 as “adipocytes area value”. (m = male, f = female, Control = controls, Halo = haloperidol-medicated, Cloz = clozapine-medicated).
Figure 3
Figure 3
Protein expression of (A) perilipin A, (B) hormone-sensitive lipase (HSL), (C) hepcidin, (D) glucose transporter 4 (Glut 4), (E) insulin receptor ß (IR ß) in male and female control, haloperidol, and clozapine-treated Sprague Dawley rats with * p ≤ 0.05, ** p ≤ 0.001 and *** p ≤ 0.0001 as significant (n = 10 animals per group). The autoradiographs and the Ponceau-stained membranes are seen in Supplement Figure S1a,b.
Figure 4
Figure 4
Schematic diagram of the organ connections (crosstalk) derived from the results of the serum [23,24], liver [24,26], hypothalamus [25], and adipose tissue examinations under clozapine medication. The explanations can be found in the text below.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Dayabandera M., Hanwella R., Ratnatunga S., Seneviratne S., Suraweera C., de Silva V.A. Antipsychotic-associated weight gain: Management strategies and impact on treatment adherence. Neuropsychiatr. Dis. Treat. 2017;13:2231–2241. doi: 10.2147/NDT.S113099. - DOI - PMC - PubMed
    1. Alonso-Pedrero L., Bes-Rastrollo M., Marti A. Effects of antidepressant and antipsychotic use on weight gain: A systematic review. Obesity Rev. 2019;20:1680–1690. doi: 10.1111/obr.12934. - DOI - PubMed
    1. Ferreira V., Grajales D., Valverde A.M. Adipose tissue as a target for second generation (atypical) antipsychotics: A molecular review. BBA Mol. Cell Biol. Lipids. 2020;1865:158534. doi: 10.1016/j.bbalip.2019.158534. - DOI - PubMed
    1. Spalding K.L., Arner E., Westermark P.O., Bernard S., Buchholz B.A., Bergmann O., Blomquist L., Hoffstedt J., Näslund E., Britton T., et al. Dynamics of fat cell turnover in human. Nature. 2008;453:783–787. doi: 10.1038/nature06902. - DOI - PubMed
    1. Vestri H.S., Maianu L., Moellering D.R., Garvey W.T. Atypical antipsychotic drugs directly impair insulin action in adipocytes: Effects on glucose transport, lipogenesis, and antilipolysis. Neuropsychopharmacology. 2006;32:765–772. doi: 10.1038/sj.npp.1301142. - DOI - PubMed

Grants and funding

All costs were borne by the general research budget of the LVR-KLinikum/Heinrich-Heine-University, Duesseldorf. Study design, data collection, data analysis, interpretation of data and manuscript preparation were not influenced by the funding body. Third-party funds were not raised.

LinkOut - more resources

-