Fasted zebrafish mimic genetic and physiological responses in mammals: a model for obesity and diabetes?

With worldwide rates of obesity and type-II diabetes increasing, it is essential to identify and understand the mechanisms involved during nutrient absorption and fuel allocation. Recent studies demonstrate that nutrients (e.g., lipids and carbohydrates) play a major regulatory role in gene transcription of glycolytic and lipogenic enzymes in addition to hormones, including insulin and glucagon. These nutrients generally exert their effects through key cellular nutrient/energy receptors. Fasting was used to identify these nutrient/energy receptors known from mammalian studies to ascertain if zebrafish (Danio rerio) are a suitable model for the study of metabolic disorders. Zebrafish were subjected to a fasting/re-feeding regime for 3 weeks, and gene expression of sterol responsive binding protein 1 and 2 (SREBP), the mammalian target of rapamycin (mTOR), cAMP response element binding protein 3-like 3 (CREB3l3), and AMP-activated protein kinase alpha (AMPKα) was assessed. Fasted zebrafish lost ∼10% of their body mass over the 3-week experiment, with an associated depression in oxygen consumption. Increases in liver AMPKα and CREB3l3 mRNA transcript level were noted, concurrent with increases in the activities of the β-oxidation and gluconeogenic markers β-hydroxyacyl CoA dehydrogenase and phosphoenolpyruvate carboxykinase, respectively. Conversely, a depression in liver mTOR and SREBP1 and 2 expression was noted, with a decrease in pyruvate kinase and alanine aminotransferase activities and decreases in liver lipid and glycogen contents. Twenty-four hours after re-feeding, zebrafish rapidly recover, and the majority of parameters return to control values. Taken together, these data suggest adult zebrafish are an appropriate model for the further study of human metabolic disorders.