Humanized CETP-ApoB100 Transgenic Mice Enable a Translational Platform for Obesity Programs Incorporating Cardiovascular Risk

The rapid evolution of obesity therapeutics—driven by incretins, multi-agonists, and emerging metabolic targets—has elevated expectations for demonstrating cardiovascular benefit in parallel with metabolic efficacy. Obesity is now recognized as a systemic disorder impacting lipid handling, vascular integrity, inflammation, and hepatic injury. As a result, cardiometabolic endpoints are increasingly considered essential components of contemporary obesity-drug development.

Conventional murine models are poorly suited for this shift. Diet-induced obesity in wildtype strains can reproduce excess adiposity but fails to generate the human-like dyslipidemia central to cardiometabolic disease. Standard strains, including C57BL/6, lack cholesteryl ester transfer protein (CETP) and exhibit HDL-dominant lipoprotein profiles that diverge markedly from the LDL-driven dyslipidemia characteristic of human obesity and cardiovascular risk.

Taconic’s CETP-ApoB100 double-transgenic mouse directly addresses this translational limitation. Expression of human CETP and human ApoB100 produces a lipoprotein environment that more accurately reflects human physiology, enabling rigorous evaluation of lipid-centric and cardiovascular-relevant pathways within obesity, metabolic syndrome, and MASH.

Why CETP-ApoB100 Is a Translational Tool for Cardiometabolic Drug Development

As obesity therapeutics advance toward dual metabolic–cardiovascular benefit claims, models lacking CETP and human-like lipoprotein architecture limit translational confidence in preclinical findings. CETP-ApoB100 transgenic mice overcome this constraint by establishing a lipoprotein profile suitable for integrated cardiometabolic assessment.

Key features include:

Use Cases Across Obesity and Metabolic-Disease Research

CETP-ApoB100 transgenic mice support study designs in which quantifying cardiometabolic risk is essential:

Early cardiovascular safety and risk assessment

Permits evaluation of LDL/HDL modulation, CETP-mediated lipid exchange, and reverse cholesterol transport in the context of obesity or metabolic dysfunction.

Mechanistic profiling of multi-organ therapeutics

Enables assessment of incretin co-agonists, amylin analogs, FGFs, and other agents on lipid metabolism, hepatic fat handling, inflammation, and vascular biology within a single platform.

Integrated cardiometabolic combination studies

Facilitates characterization of additive or synergistic effects between metabolic therapies and lipid-lowering or anti-inflammatory agents, with longitudinal lipid, hepatic, and vascular readouts.

By aligning human-like lipoprotein biology with flexible metabolic-disease modeling, CETP-ApoB100 transgenic mice allow investigators to connect weight-loss mechanisms with downstream cardiovascular consequences in a single, translationally relevant system.

Case Studies Demonstrating Cardiometabolic Utility

Hansen et al., 2010

This foundational characterization established how human CETP and human ApoB100 expression fundamentally alters murine lipid biology. The double-transgenic system exhibits elevated LDL, reduced HDL, and robust CETP activity—features that recapitulate essential aspects of human dyslipidemia. Although dietary challenges were not applied, the authors identified them as a critical next step for revealing the model’s atherogenic capacity. This work established the mechanistic foundation for using the CETP–ApoB100 mouse to interrogate lipid biology in cardiometabolic disease.

Briand et al., 2012

In obese, insulin-resistant CETP–ApoB100 mice, sitagliptin enhanced reverse cholesterol transport by increasing macrophage-derived cholesterol excretion despite minimal changes in HDL-C or total cholesterol. These results illustrate the model’s sensitivity for detecting functionally meaningful lipid-trafficking shifts that remain unobservable in CETP-deficient strains. For obesity-drug developers, this underscores the importance of assessing lipid biology beyond classical metabolic parameters.

Canali et al., 2024

Using an amylin-based diet to induce obesity, steatosis, inflammation, and dyslipidemia, investigators demonstrated that an IL-22–encoding mRNA–LNP therapy improved body weight, lipid parameters, and liver pathology in CETP/ApoB100 mice. The study highlights the model’s utility for integrated assessments of metabolic, hepatic, and lipid-centric endpoints within a single system—an approach that aligns with modern obesity-program expectations for demonstrating cardiometabolic benefit.

Conclusion: A Purpose-Built Translational System for Modern Obesity Research

As obesity programs increasingly pursue cardiovascular-risk modification alongside metabolic efficacy, preclinical models must more faithfully reflect human lipoprotein physiology. The humanized CETP-ApoB100 transgenic model provides this capability through:

• Human-like lipoprotein dynamics
• Compatibility with contemporary metabolic-disease diets
• Cardiovascular-relevant functional and mechanistic readouts
• Multi-system phenotyping across metabolic, hepatic, and vascular endpoints

For teams developing next-generation metabolic and cardiometabolic therapies, the humanized CETP-ApoB100 transgenic model offers a strategic, translationally aligned platform that reduces uncertainty and strengthens the path from discovery to clinical development.