Obese zebrafish: A small fish for a major human health condition

Abstract

Obesity is becoming a silent worldwide epidemic, with a steady increase in both adults and children. To date, even though several drugs have been licensed for long-term obesity treatment, none of them are yet used in routine clinical practice. So far the only successful intervention has been behavioral therapy. A suitable and economic experimental model mimicking the human condition would therefore be extremely useful to evaluate preventive measures and novel treatments. Zebrafish are emerging as an important model system to study obesity and related metabolic disease. Remarkable similarities have been reported in lipid metabolism and the adipogenic pathway between zebrafish and mammals. Moreover, the zebrafish possesses a number of features-the relative inexpensiveness of animal husbandry, its optical transparency and the ability to produce a large number of offspring at low cost-that make it ideal for large-scale screening and for testing drugs and intervention. In this review, we summarize recent progress in using zebrafish as a model system to study obesity and obesity-related metabolic disorders. We describe several zebrafish models (in both larvae and adult animals) that develop obesity and non-alcoholic fatty liver disease (NAFLD) using different approaches, including gene manipulation, diet manipulation and modification of microbiota composition. For these models, we have outlined the specific aspects related to obesity and its development and we have summarized their advantages and limitations.

Keywords: NAFLD; inflammation; metabolic diseases; obesity; zebrafish.

Figure 1

Zebrafish models of obesity and obesity‐related disease. Several different approaches, including diet‐induced obesity (blue), and mutant (green) and transgenic (red) models, are used in zebrafish to study the pathways involved in obesity development and progression. Proadipogenic and antiadipogenic pathways are described and used in order to characterize this condition at the molecular level. Increased adipose tissue (AT) causes a rise in free fatty acids (FFAs) that determines ectopic fat deposition and inflammation. Both phenomena collaborate in inducing obesity‐related diseases. Microbiota dysbiosis is involved by promoting obesity development and inflammation. Transgenic models of lipid accumulation in the liver, which resemble the human condition, were also developed in zebrafish but they failed to induce obesity

Figure 2

Zebrafish mutant models of obesity and fat distribution. Several mutant models in zebrafish are available in order to study the pathways involved in obese phenotypes. The signaling of different models is shown in the figure: (A) vizzini, (B) cyp2r1 ^−/−, (C) mc4r ^−/−, (D) lepr ^−/−, (E) leprsa1508/sa1508, (F) PLXND1‐null. The main effects of these pathways are connected to regulation of lipid metabolism, control of energy balance, distribution of body fat and/or sensitivity to insulin