Fatty Zucker Rat Modeling & Pharmacodynamics Service

Creative Biolabs is at the forefront of this research, offering a variety of well-established rodent models, including the fatty Zucker rat, to precisely evaluate the efficacy of novel compounds against atherosclerosis and related metabolic pathologies.

Introduction

Atherosclerosis, a chronic inflammatory disease of the arteries, is a leading cause of cardiovascular morbidity and mortality worldwide. Its progression is significantly influenced by metabolic disorders such as obesity, dyslipidemia, and type 2 diabetes mellitus (T2DM). Understanding the intricate links between these conditions and developing effective therapeutic strategies requires robust preclinical models.

Fatty Zucker Rats Model

The fatty Zucker rat (ZFR), specifically the fa/fa genotype, is a widely recognized and spontaneously obese rodent model invaluable for metabolic research. This model naturally develops a comprehensive metabolic syndrome phenotype, including obesity, insulin resistance, dyslipidemia, and often progresses to T2DM. The ZFR's utility extends to studying associated complications such as non-alcoholic fatty liver disease (NAFLD), cardiac dysfunction, and pulmonary hypertension, making it a highly relevant tool for investigating the multifaceted aspects of metabolic disease.

Fig.1 The cardiovascular dynamics in Zucker diabetic fatty (ZDF) rats.^1,3

Model Construction Steps

The ZFR model originates from a spontaneous autosomal recessive mutation in the leptin receptor gene (Lepr), leading to a non-functional leptin receptor and a foundational defect in energy balance regulation. This defect drives the ZFR's characteristic metabolic abnormalities.

Maintaining ZFR colonies involves perpetuating the fa/fa genotype, as homozygous animals are phenotypically obese and display full metabolic syndrome, while heterozygous (fa/+) animals appear lean but carry the recessive allele.

Strengths and Limitations

Strengths:

• Spontaneous Development: ZFRs spontaneously develop obesity, insulin resistance, and T2DM, mirroring human metabolic syndrome progression.
• Comprehensive Phenotype: Exhibits hyperphagia, dyslipidemia, hypertension, hepatic steatosis, and can develop cardiac/renal complications, offering a broad study scope.
• Relevance to T2DM & NAFLD: A gold standard for evaluating anti-diabetic and anti-NAFLD/NASH compounds.
• Cardiac & Pulmonary Insights: Useful for investigating cardiac lipid accumulation and pulmonary hypertension in metabolic dysfunction.
• Genetic Basis: The clear genetic defect (leptin receptor mutation) provides a defined mechanistic understanding.

Limitations:

• Atherosclerosis Development: While useful for metabolic risk factors, ZFRs typically do not spontaneously develop advanced atherosclerotic plaques like dedicated atherosclerosis models (e.g., ApoE-deficient mice) without interventions.
• Kidney Disease: Renal impairment is present, but molecular resemblance to human chronic kidney disease (CKD) may be limited in some aspects, requiring careful consideration for specific CKD studies.
• Leptin Resistance: The primary defect is leptin resistance, which may not be the sole or primary driver of metabolic disease in all human patients.

Evaluation Platform

Creative Biolabs provides a state-of-the-art evaluation platform to thoroughly assess therapeutic efficacy in the ZFR model. Our capabilities span a wide range of analytical techniques, ensuring robust and interpretable data for your preclinical studies.

Key Test Indicators and Methodologies:

• Biochemical Analysis: Glucose, insulin, HbA1c, lipid profiles (triglycerides, cholesterol), free fatty acids, liver enzymes (ALT, AST), kidney function markers (creatinine, BUN).
• Molecular Analysis: Gene expression (qPCR), protein expression (Western blot, ELISA) in target tissues.
• Cellular Analysis: Flow cytometry for immune cell profiling, β-cell mass.
• Histopathology: H&E, Masson's trichrome, Oil Red O, immunohistochemistry for inflammation, fibrosis, lipid accumulation in organs.
• Physiological Measurements: Body weight, food intake, glucose/insulin tolerance tests (OGTT, ITT), blood pressure, heart rate, echocardiography, pulmonary arterial pressure.

Applications

• Simulating Diseases: Obesity, T2DM, insulin resistance, metabolic syndrome, NAFLD, non-alcoholic steatohepatitis (NASH), cardiac dysfunction (e.g., cardiac lipotoxicity, atherosclerosis), pulmonary hypertension, and diabetic nephropathy.
• Evaluating Drugs: Anti-obesity agents, insulin sensitizers, anti-diabetic compounds, lipid-lowering drugs, anti-inflammatory agents, anti-fibrotic therapies, and novel compounds targeting metabolic pathways.
• Studying Treatment Approaches: Dietary interventions, exercise regimens, bariatric surgery mimetics, and combination therapies aimed at improving metabolic health and preventing complications.

Related Atherosclerosis Models

• ApoE^-/- Mice Model
• Low-Density Lipoprotein Receptor-Deficient Mice (LDLR^-/-) Model
• ApoE*3 Transgenic (E3L) Mice Model
• Carotid Artery Endothelial Denudation Model
• High-Fat-Diet (HFD) & CHOL-Induced Aorta Atherosclerosis Model
• Blood Flow-Induced Arterial Intimal Thickening Model

Our Advantages

• Decades of Expertise: Benefit from our extensive experience in metabolic disease research and ZFR model utilization.
• Customized Study Design: Tailored protocols to precisely meet your unique research objectives.
• High-Quality, Consistent Models: Meticulously characterized ZFRs ensure reliable and reproducible results.
• Comprehensive Data Delivery: Rigorous analysis and clear, actionable reports support your decision-making.
• State-of-the-Art Facilities: Access to advanced analytical platforms for in-depth mechanistic insights

Work with Us

Contact Us

Creative Biolabs is committed to providing comprehensive preclinical research services utilizing the ZFR model. Our expertise can guide your drug discovery and development efforts in metabolic diseases. Contact us today to discuss how we can support your next project.

FAQs

1. Q1: What are the primary cardiovascular complications observed in ZFRs?

   A: ZFRs often develop cardiovascular complications linked to metabolic dysfunction, including hypertension, dyslipidemia-induced cardiac changes, and cardiac lipid accumulation. They are also used to study pulmonary hypertension in obesity and diabetes contexts.

2. Q2: What are the main differences between ZFRs and lean Zucker Littermates (ZLs)?

   A: The key difference is the leptin receptor gene mutation. ZFRs are homozygous (fa/fa) for the mutation, causing leptin resistance and metabolic syndrome, while ZLs are heterozygous (fa/+) or wild-type, serving as healthy controls.

3. Q3: How do you ensure the quality and consistency of its ZFR models?

   A: We ensure quality through meticulous ZFR colony maintenance via controlled breeding. We implement strict quality control, including genetic verification and regular phenotypic assessment, guaranteeing consistent and reproducible models for your research.

4. Q4: What types of endpoints can be measured in a ZFR study at Creative Biolabs?

   A: We offer diverse endpoints, including metabolic parameters (glucose, insulin, lipids), organ function markers, inflammatory markers, and comprehensive histopathological assessments. Physiological tests like glucose and insulin tolerance are also performed.

5. Q5: Can you customize ZFR study protocols to meet specific research needs?

   A: Absolutely. Our expert team collaborates closely with clients to design and implement customized study protocols. This ensures the experimental design perfectly aligns with your specific research questions and therapeutic objectives.

Published Data

Fig.2 Hemodynamics and right ventricular hypertrophy of ZDF rats.^2.3

This study utilized the ZDF rat model to investigate the relationship between metabolic dysfunction and pulmonary hypertension. Researchers observed that ZDF rats, characterized by obesity, insulin resistance, and hyperglycemia, developed elevated pulmonary arterial pressures, right ventricular hypertrophy, and pulmonary arterial medial thickening. This research highlights the ZFR model's utility in exploring the complex interplay between systemic metabolic disorders and specific organ complications like pulmonary vascular disease. The findings underscore the model's value for therapeutic development in related areas.

References

1. Otani, Kosuke et al. "Cardiovascular Characteristics of Zucker Fatty Diabetes Mellitus Rats, an Animal Model for Obesity and Type 2 Diabetes." International journal of molecular sciences vol. 23,8 4228. 11 Apr. 2022. https://doi.org/10.3390/ijms23084228
2. Morales-Cano, Daniel et al. "Elevated pulmonary arterial pressure in Zucker diabetic fatty rats." PloS one vol. 14,1 e0211281. 28 Jan. 2019. https://doi.org/10.1371/journal.pone.0211281
3. Distributed under Open Access license CC BY 4.0, without modification.

For Research Use Only.