Liver immune responses to inflammatory stimuli in a diet-induced obesity model of zebrafish

Abstract

Obesity-and metabolic syndrome-related diseases are becoming important medical challenges for the western world. Non-alcoholic fatty liver disease (NAFLD) is a manifestation of these altered conditions in the liver, and inflammation appears to be a factor that is tightly connected to its evolution. In this study, we used a diet-induced obesity approach in zebrafish (Danio rerio) based on overfeeding to analyze liver transcriptomic modulation in the disease and to determine how obesity affects the immune response against an acute inflammatory stimulus such as lipopolysaccharide (LPS). Overfed zebrafish developed an obese phenotype, showed signs of liver steatosis, and its modulation profile resembled that observed in humans, with overexpression of tac4, col4a3, col4a5, lysyl oxidases, and genes involved in retinoid metabolism. In response to LPS, healthy fish exhibited a typical host defense reaction comparable to that which occurs in mammals, whereas there was no significant gene modulation when comparing expression in the liver of LPS-stimulated and non-stimulated obese zebrafish at the same statistical level. The stimulation of obese fish represents a double-hit to the already damaged liver and can help understand the evolution of the disease. Finally, a comparison of the differential gene activation between stimulated healthy and obese zebrafish revealed the expected difference in the metabolic state between healthy and diseased liver. The differentially modulated genes are currently being studied as putative new pathological markers in NAFLD-stimulated liver in humans.

Inflammatory diseases modelling in zebrafish

“…Weight gain; increased BMI; triglycerides accumulation; adipocyte hyperplasia; ectopic adipose tissue; increased expression of adiponectin, adiponectin receptors, leptin receptor; increased inflammatory molecules TNFα, IL1β, MMP2 and MMP9 [104] DIO models Artemia overfeeding Adult Overfeeding with nauplii artemia for 8 wk Increased BMI; high plasma triglycerides; hepatosteatosis [106] Chow overfeeding Adult Overfeeding with standard fish chow for 8 mo Weight gain; hepatosteatosis [109] Zebrafish obesogenic test (OZ) Larva High-fat diet based in hardboiled chicken egg-yolk ad libitum during one day…”

“…adult zebrafish was generated by feeding them two times the standard fish chow than the controls [109] . DIO animals showed increased total weight, showed liver steatosis, as well as the overexpression of tac4, col4a3, col4a5, lysyl oxidases and genes involved in retinoid metabolism.…”

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“…[17] Another animal model, such as zebra fish have been observed as an obesity model and this model is very appropriate to be developed as an obesity model through high-fat diet administration. [8][9][10][11][12][13][14][15][16][17][18] In the recent study, we use zebra fish (D. rerio) to explore the association between high-fat diet consumption, obesity, and metabolic syndrome. The results of this study found that high-fat-diet-induced obesity in zebrafish has an impact on elevated metabolic syndrome and the development of NAFLD.…”

Zebrafish Aging Models and Possible Interventions

“…Zebrafish, like humans, will overeat if exposed to large amounts of food [98]. Although studies have examined the effects of overfeeding in zebrafish [99][100][101], few studies have utilized these animals as a model to study obesity, and to a lesser extent to study the effects of brain aging.…”