Generation and characterization of a humanized PPARδ mouse model

Area of Science:

• Pharmacology
• Metabolic Diseases
• Immunology

Background:

• The nuclear receptor peroxisome proliferator-activated receptor delta (PPARδ) plays a role in lipid metabolism and inflammation.
• Understanding species-specific differences in PPARδ function is crucial for drug development.

Purpose of the Study:

• To generate humanized mice for PPARδ (PPARδ KI mice) to investigate functional differences between mouse and human PPARδ.
• To assess the utility of PPARδ KI mice for early drug efficacy assessment.

Main Methods:

• Human PPARδ function was evaluated in PPARδ KI mice under various conditions, including fasting and challenge with the GW0742 compound.
• Mice were fed either a chow diet or a high-fat diet (HFD).
• Gene expression profiling was performed in liver, muscle, and macrophages.

Main Results:

• PPARδ KI mice exhibited hypomorphic expression of human PPARδ in several tissues, with minor effects on lipid parameters.
• Plasma metabolic parameters and responses to fasting or GW0742 treatment were similar between PPARδ KI and wild-type mice.
• Gene expression patterns regulated by human and mouse PPARδ were comparable, as was the anti-inflammatory potential.

Conclusions:

• Human PPARδ can effectively compensate for mouse PPARδ in regulating lipid metabolism and inflammation.
• The PPARδ KI mouse model demonstrates responsiveness to pharmacological challenges and is a useful tool for preclinical evaluation of PPARδ activators.