{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T05:42:38Z","timestamp":1775108558434,"version":"3.50.1"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>This review examines how olanzapine drives metabolic injury beyond the brain and why an organ-resolved perspective is needed. We synthesize clinical signals of early weight gain, insulin resistance, dyslipidemia, and steatotic liver disease, and integrate translational evidence across liver, adipose tissue, skeletal muscle, pancreatic \u03b2-cells, and the gut\u2013liver axis. Mechanistic strands include disordered hepatic lipid handling, suppression of brown-fat thermogenesis, \u03b2-cell endoplasmic-reticulum stress with impaired secretion, and skeletal-muscle insulin-signaling defects with altered epigenetic programs that blunt glucose disposal. We summarize modifiers of risk across life stage, treatment exposure, genetic variation, smoking status, and pregnancy, and distill a pragmatic pathway that prioritizes early reassessment, MASLD-aligned liver evaluation, targeted lifestyle treatment, metformin for early deterioration, and GLP-1 receptor agonists when required. We advance the view that weight-independent extra-cerebral mechanisms are central to olanzapine\u2019s metabolic liability and that psychiatric practice should adopt metabolic frameworks used in hepatology and endocrinology. We propose an agenda for organ-specific human phenotyping and exposure-aware designs that integrate therapeutic drug monitoring with microbiome, metabolomics, and bile-acid profiling, alongside comparative trials that test stepped algorithms within psychiatric care. This perspective outlines a path to preserve antipsychotic efficacy while reducing preventable systemic metabolic harm.<\/jats:p>","DOI":"10.3389\/fphar.2025.1729264","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T04:16:56Z","timestamp":1775103416000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Olanzapine and peripheral metabolic dysregulation: organ-resolved mechanisms, risk, and MASLD-aligned care pathways"],"prefix":"10.3389","volume":"16","author":[{"given":"Shuwei","family":"Weng","sequence":"first","affiliation":[{"name":"Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Key Laboratory of Metabolic Heart Disease in Fujian Province, Clinical Research Centre of Metabolic Cardiovascular Disease in Fujian Province","place":["Fuzhou, China"]},{"name":"Cardiovascular Department, National Regional Medical Center, Binhai Branch of the First Affiliated Hospital, Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinjxiu","family":"Lin","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Key Laboratory of Metabolic Heart Disease in Fujian Province, Clinical Research Centre of Metabolic Cardiovascular Disease in Fujian Province","place":["Fuzhou, China"]},{"name":"Cardiovascular Department, National Regional Medical Center, Binhai Branch of the First Affiliated Hospital, Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dajun","family":"Chai","sequence":"additional","affiliation":[{"name":"Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Key Laboratory of Metabolic Heart Disease in Fujian Province, Clinical Research Centre of Metabolic Cardiovascular Disease in Fujian Province","place":["Fuzhou, China"]},{"name":"Cardiovascular Department, National Regional Medical Center, Binhai Branch of the First Affiliated Hospital, Fujian Medical University","place":["Fuzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1038\/mp.2010.33","article-title":"Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis","volume":"16","author":"Albaugh","year":"2011","journal-title":"Mol. 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