Zebrafish Models for Screening of Metabolic Diseases

Abstract

Metabolic diseases such as type 2 diabetes, coronary heart disease, and obesity are the leading cause of morbidity and mortality. In the drug discovery process, many preclinical screening models exist. However, in silico approaches result in increased number of molecules which amplifies a substantial load on preclinical screening. Furthermore, newer targets of metabolic diseases are evolving. This prompts for use of high throughput in vitro screening and alternative models which can mimic lipid metabolism, pancreas structure, and glucose homeostasis.

Zebrafish is one such alternative model for diseases with a high degree of genetic, anatomical, and physiological similarities to humans. The ease of accessibility to embryonic and genetic manipulations, optical transparency of its embryos, relative short generation time, and facile maintenance make zebrafish an ideal model for screening of metabolic diseases.

Obesity is the root cause of many metabolic diseases. Overnutrition of zebrafish larvae and juveniles activates mTOR, suppresses notch signaling, and increases β-cell mass in tune with the increased requirement of insulin resembling changes in human obesity.

Diabetes is one of the prominent metabolic diseases with impaired glucose homeostasis. The morphology and cellular architecture, signaling pathways, and mechanisms of zebrafish pancreas with distinctive exocrine and endocrine compartments mimic the mammalian pancreas. The chief organ systems brain, liver, adipose tissue, and skeletal muscles, which are the systems of glucose homeostasis, are also intact in zebrafish which makes it an ideal model for screening of metabolic diseases. Transgenic models of insulin resistance in skeletal muscles and knockdown of liver-specific insulin receptors are available to screen type 2 diabetes. Though chemically induced models of type 1 diabetes are reported, the innate ability of zebrafish to regenerate β-cell is interfered and hence is a challenge. Zebrafish models to screen maturity-onset diabetes of young (MODY) are also achievable with targeted single gene mutation. Repeated blood collection to measure glucose, IGTT, fluorescent protein expression, and β-cell regeneration research are precisely established. The models to screen diabetic complications such as diabetic retinopathy, neuropathy, nephropathy, microvascular complications, impaired wound healing, and bone mineralization are developed in zebrafish models.

Chronic increased serum cholesterol and triacylglycerol are hallmarks of atherosclerosis. A specialized system of absorption, transportation, synthesis, and storage of lipids is present in humans. Presence of LDL receptor, lipid trafficking genes, lipoprotein-modifying enzymes, β-dominant fasting lipoprotein profile, molecular and cellular mechanisms similar to human lipoprotein biology makes zebrafish a relevant model to mimic hyperlipidemia. High cholesterol diets, deletion of apoc2 gene, and liver x receptor (LXR) deletion are few established models of hyperlipidemia. In addition to hyperlipidemia, formation of granulomas from macrophages as immune-induced inflammatory host response in zebrafish is promising in the development of atherosclerosis.

The optical transparency, ease of genetic manipulations, mimicking human structures and functions, high throughput, ability to develop diabetic complications in days are the advantages of using zebrafish for metabolic models. The limitation of zebrafish is the scientific validation of some of the models with respect to reversal upon treatment with drugs, which will be achieved in due course of time.