Zebrafish Models to Study Metabolic Diseases and Accelerate Preclinical Drug Discovery

Metabolic diseases such as obesity and type 2 diabetes represent an increasing challenge for global health systems. The global burden of metabolic disease has risen sharply over the past decades, not only due to higher mortality, but also because millions of people live for years with chronic metabolic dysfunction. In 2021, type 2 diabetes and obesity together accounted for more than 200 million years of healthy life lost worldwide, reflecting a sustained and accelerating global impact. 

This growing burden highlights the need for experimental models able to capture systemic metabolic alterations and support efficient preclinical drug discovery. In this context, zebrafish have emerged as a valuable vertebrate model combining physiological relevance with experimental scalability.

Why Zebrafish Are a Powerful Model for Studying Metabolic Diseases

Zebrafish share a high degree of genetic and physiological conservation with humans, with approximately 70% of human genes and over 80% of disease-related genes having identifiable zebrafish orthologs. Importantly, key metabolic pathways involved in glucose homeostasis, insulin signaling, lipid metabolism, and adipogenesis are evolutionarily conserved. This conservation allows zebrafish to recapitulate central features of human metabolic diseases in a whole-organism context.

From a biological perspective, zebrafish possess the essential organs required for metabolic regulation, including the pancreas, liver, skeletal muscle, adipose tissue, and central nervous system. Their endocrine pancreas shows strong structural and developmental similarity to mammals, with insulin-producing β-cells, glucagon-secreting α-cells, and conserved hormonal regulation of blood glucose. The temporal sequence of pancreatic development in zebrafish closely parallels that observed in humans, reinforcing their relevance for diabetes research.

Technical advantages further strengthen their utility. Zebrafish embryos develop externally and remain optically transparent during early life stages, enabling direct, non-invasive visualization of metabolic organs and cellular dynamics in vivo. Their high fecundity and small size facilitate the generation of large experimental cohorts, supporting statistically robust studies and scalable screening designs. Moreover, genetic manipulation using CRISPR/Cas9 and transgenesis allows precise modeling of disease-associated genes involved in metabolic regulation.

These combined features make zebrafish particularly suited to dissect genetic mechanisms underlying metabolic dysfunction and to evaluate potential drug candidates in early preclinical stages.

Zebrafish Phenotypes for Obesity, Diabetes, and Metabolic Syndrome

Zebrafish models have been successfully established to reproduce key phenotypes associated with human metabolic disorders. Diet-induced obesity paradigms lead to increased adiposity, visceral fat accumulation, hepatic steatosis, and dysregulation of conserved lipid metabolism pathways. These phenotypes mirror essential features of obesity and allow evaluation of metabolic imbalance at the organism level.

Zebrafish models have been successfully established to mimic major metabolic disease phenotypes observed in humans. Obesity models rely on both dietary and genetic approaches. Contrary to rodents, whose diet can only be manipulated 3 weeks after birth, when weaning occurs, zebrafish can be overfed from 5 days post-fertilization (dpf). 

Overnutrition and high-fat diet paradigms induce increased adiposity, hypertriglyceridemia, hepatic steatosis, and dysregulation of conserved metabolic regulators such as pparg, srebp, and lepr. Zebrafish develop distinct adipose depots, including visceral and subcutaneous fat, mirroring mammalian fat distribution and enabling investigation of depot-specific metabolic risk.

Figure 1. Outline showing various applications of zebrafish in the field of cardiovascular disease and metabolic disease. Adapted from: Angom RS, Nakka NMR. Zebrafish as a Model for Cardiovascular and Metabolic Disease: The Future of Precision Medicine. Biomedicines. 2024 Mar 20;12(3):693.

Importantly, zebrafish obesity models reproduce the differential metabolic consequences associated with fat distribution. Diet-induced obesity can result in either metabolically healthy or unhealthy phenotypes, depending on nutrient composition, reflecting patterns also observed in human populations. This allows researchers to study obesity-related insulin resistance and progression toward metabolic syndrome within a controlled experimental framework.

Diabetes models in zebrafish capture key hallmarks of both type 1 and type 2 diabetes. Hyperglycemia, insulin resistance, and β-cell dysfunction can be induced through genetic modification, dietary manipulation, glucose immersion, chemical ablation, or targeted β-cell injury. These approaches reproduce fundamental aspects of diabetic pathophysiology, including impaired insulin signaling and altered glucose tolerance.

At ZeClinics, we have developed metabolic disorder and obesity models using controlled dietary interventions in zebrafish juveniles. Juvenile zebrafish are fed a Control Diet (CD) or High Fat Carbs (HFC) diet for 20 days in the desired background. This model enables quantitative assessment of whole-body adiposity, fat distribution, and liver lipid accumulation, providing reproducible readouts relevant for metabolic research (Figure 2). As the disease progresses, liver inflammation and fibrosis are observed, reflecting the ongoing progression towards Metabolic Dysfunction-Associated Steatohepatitis (MASH). In addition, biochemical – e.g., triglycerides – and/or omic levels – Transcriptomic, Proteomic, and Metabolomics – can be integrated with morphological and imaging-based analyses, allowing a multidimensional characterization of metabolic status. An article describing the method and pharmacological validation of this model is currently under revision in Nature Metabolism.

Figure 2. Lipid accumulation model in juvenile fish. Fish are fed for 20 days with a Control Diet (CD) or a High-Fat Carbohydrate diet (HFC). A) Staining of fish adipocytes with a fluorescent dye for evaluation of fat accumulation and distribution. Abdominal fat accumulation is observed in fish fed with HFC. B) Abdominal fat quantification. Fluorescence intensity measurement was done in the individual under different diets. Statistical analyses have shown significant differences between CD and HFC. Means and eSEM are plotted. ***p<0.001 vs CD.

Applications of Zebrafish Models in Metabolic Drug Screening

Diet-induced obesity models in zebrafish have been widely applied to evaluate the metabolic effects of pharmacological compounds in vivo. Their capacity to rapidly induce adiposity and generate quantifiable whole-body readouts makes them particularly suitable for early-stage drug screening.

A representative example is the study conducted by Tingaud-Sequeira et al., in which zebrafish larvae were overfed with egg yolk powder to induce increased adiposity and subsequently subjected to a 24-hour fasting period prior to compound exposure. This experimental design enabled direct assessment of drug-induced modulation of lipid storage at the whole-organism level. Using this model, the authors demonstrated that two peroxisome proliferator-activated receptor gamma (PPARγ) agonists, rosiglitazone and tributyltin (TBT), significantly increased adiposity by promoting adipocyte hypertrophy, identifying these compounds as obesogenic. In contrast, treatment with a PPARγ antagonist and an α1-adrenergic receptor agonist, both known to stimulate lipolysis, resulted in reduced lipid accumulation, revealing clear anti-obesogenic effects.

Further evidence supporting the translational relevance of zebrafish obesity models was provided by Zhou et al., who performed proof-of-principle drug testing using a comparable diet-induced obesity paradigm. In this study, five hypolipidemic drugs approved for human use were evaluated in zebrafish, and all exhibited significant lipid-lowering effects consistent with their known clinical activity. The concordance between zebrafish and human responses reinforced the predictive value of these models for metabolic drug screening.

Together, these studies demonstrate that zebrafish obesity models can reliably capture pharmacological modulation of lipid metabolism in vivo. Their compatibility with quantitative imaging, rapid experimental timelines, and whole-organism readouts positions zebrafish as a valuable platform for screening compounds targeting metabolic dysfunction during early preclinical development.

Source

Angom RS, Nakka NMR. Zebrafish as a Model for Cardiovascular and Metabolic Disease: The Future of Precision Medicine. Biomedicines. 2024 Mar 20;12(3):693.doi: 10.3390/biomedicines12030693.

Shamsnia HS, Faramarzi MA, Abdolghaffari AH, Mojtabavi S. Zebrafish as an effective model for accelerating diabetes research from discovery to therapy. J Diabetes Metab Disord. 2025 Oct 13;24(2):224. doi: 10.1007/s40200-025-01760-z.

Tingaud-Sequeira A, Ouadah N, Babin PJ. Zebrafish obesogenic test: a tool for screening molecules that target adiposity. J Lipid Res. 2011 Sep;52(9):1765-72. doi: 10.1194/jlr.D017012. 

Zang L, Maddison LA, Chen W. Zebrafish as a Model for Obesity and Diabetes. Front Cell Dev Biol. 2018 Aug 20;6:91. doi: 10.3389/fcell.2018.00091. 

Zhang H, Zhou XD, Shapiro MD, Lip GYH, Tilg H, Valenti L, Somers VK, Byrne CD, Targher G, Yang W, Viveiros O, Opio CK, Mantzoros CS, Ryan JD, Kok KYY, Jumaev NA, Perera N, Robertson AG, Abu-Abeid A, Misra A, Wong YJ, Ruiz-Úcar E, Ospanov O, Kızılkaya MC, Luo F, Méndez-Sánchez N, Zuluaga M, Lonardo A, Al Momani H, Toro-Huamanchumo CJ, Adams L, Al-Busafi SA, Sharara AI, Chan WK, Abbas SI, Sookoian S, Treeprasertsuk S, Ocama P, Alswat K, Kong AP, Ataya K, Lim-Loo MC, Oviedo RJ, Szepietowski O, Fouad Y, Zhang H, Abdelbaki TN, Katsouras CS, Prasad A, Thaher O, Ali A, Molina GA, Sung KC, Chen QF, Lesmana CRA, Zheng MH. Global burden of metabolic diseases, 1990-2021. Metabolism. 2024 Nov;160:155999. doi: 10.1016/j.metabol.2024.155999.

Zhou J, Xu YQ, Guo SY, Li CQ. Rapid analysis of hypolipidemic drugs in a live zebrafish assay. J Pharmacol Toxicol Methods. 2015 Mar-Apr;72:47-52. doi: 10.1016/j.vascn.2014.12.002.

By Javier Terriente

Javier is the co-founder of ZeClinics and ZeCardio Therapeutics, two biotech firms specializing in zebrafish-based preclinical drug discovery for cardiovascular, neural, and toxicology applications. He combines scientific leadership with business acumen, having successfully driven fundraising efforts and strategic partnerships.

Currently leading scientific efforts at ZeCardioTx (and formerly CSO at ZeClinics), Javier also serves on the Board of Directors of AseBio, where he advocates for industry collaboration. His academic background includes a PhD in Molecular Biology and a Marie Curie Fellowship. Recognized as an expert in zebrafish models, he has published extensively and has supervised five industrial PhD theses.