Citalopram modulates hypothalamic appetite-related signalling and hepatic lipid metabolism in rainbow trout

Citalopram, a selective serotonin reuptake inhibitor prescribed for depression in humans, is increasingly detected in freshwater ecosystems alongside other contaminants of emerging concern, posing risks to non-target species. Here, we investigated the impact of citalopram on appetite regulation and hepatic energy metabolism in rainbow trout (Oncorhynchus mykiss) using two exposure routes: chronic dietary administration (0.01 and 0.02 μg/g feed for 10 days) and acute intraperitoneal injection (10 μg/g bw). Plasma metabolite (glucose, lactate, triglyceride, and non-esterified fatty acids-NEFAs-) levels, mRNA abundance of appetite-regulating factors in hypothalamus and gastrointestinal tract, and hepatic enzyme activities and mRNA abundance related to glucose and lipid metabolism were assessed. Both exposure routes upregulated hypothalamic npy (neuropeptide Y) mRNA abundance-a potent orexigenic factor-, while intraperitoneal injection additionally downregulated anorexigenic pomca1 (pro-opiomelanocortin), suggesting an orexigenic nature of citalopram, though with divergent modulation of energy sensors and transcription factors (prkaa2-AMP-activated protein kinase α2, Ampkα2-, mtor-mechanistic target of rapamycin-, and creb1-cAMP response element-binding protein-). Dietary exposure increased hepatic ATP-citrate lyase (Acly) mRNA and activity, whereas intraperitoneal administration upregulated fasn (fatty acid synthase) but downregulated cpt1b (carnitine palmitoyltransferase 1) and pklr (pyruvate kinase, Pk) levels, favoring lipogenesis over fatty acid oxidation. Dietary citalopram did not affect plasma metabolites, whereas intraperitoneal injection induced hyperglycemia and reduced NEFAs. Collectively, these findings demonstrate that citalopram exposure subtly reshapes neuroendocrine appetite regulation and hepatic lipid metabolism in rainbow trout in a route-dependent manner. These alterations may have ecological implications for fish populations in polluted habitats.