BACKGROUND: Antipsychotics are indispensable in the treatment of severe mental illneses, however adverse metabolic effects including diabetes, weight gain, dyslipidemia, and related cardiovascular morbidity are common, and current pharmacological strategies for their management are unsatisfactory. Glucagon-like 1 peptide receptor agonists (GLP-1 RAs) are approved for the treatment of type 2 diabetes and obesity hold promise for the management of antipsychotic-associated adverse metabolic effects. METHODS: To characterize the molecular effects and identify biomarkers for GLP-1 RA preventive treatment, Sprague-Dawley female rats were treated with long-acting formulations of the antipsychotic olanzapine and the GLP-1 RA dulaglutide for 8 days. A pair-feeding protocol evaluated the combined effects of dulaglutide and food restriction on an olanzapine-induced metabolic phenotype. Body weight and food consumption were recorded. Biochemical analysis included a lipid profile, a spectrum of gastrointestinal and adipose tissue-derived hormones, and fibroblast growth factor 21 serum levels. RESULTS: Olanzapine induced hyperphagia, weight gain, increased serum triglycerides and HDL cholesterol. Food restriction affected the OLA-induced phenotype but not serum markers. Dulaglutide led to a modest decrease in food intake, with no effect on weight gain, and did not reverse the OLA-induced changes in serum lipid parameters. Concomitant dulaglutide and food restriction resulted in weight loss, decreased feed efficiency, and lower total and HDL cholesterol. CONCLUSIONS: A combined strategy of dulaglutide and food restriction manifested a massive synergistic benefit. GLP-1RAs represent a promising strategy and deserve thorough future research. Our findings underline the potential importance of lifestyle intervention in addition to GLP-1 RA treatment.

Department of Clinical Science Faculty of Medicine University of Bergen Bergen Norway Department of Medical Biochemistry and Pharmacology Haukeland University Hospital Bergen Norway; Section of Clinical Pharmacology Department of Medical Biochemistry and Pharmacology Haukeland University Hospital Bergen Norway

Department of Pharmacology and Toxicology Faculty of Pharmacy Masaryk University Brno Czech Republic

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic; Institute of Scientific Instruments of the Czech Academy of Sciences Brno Czech Republic

Research Centre for Toxic Compounds in the Environment Faculty of Science Masaryk University Brno Czech Republic; Department of Physical Activities and Health Faculty of Sports Studies Masaryk University Kamenice 5 Brno 62500 Czech Republic

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