Document Type
Article
Publication Date
9-26-2025
Original Citation
Applegate C,
Kang Y,
Deng H,
Chen D,
Gonzalez Medina N,
Cui Y,
Feng Y,
Kuo C,
Shahoei S,
Kim H,
Vidana Gamage H,
Wallig M,
Nelson E,
Swanson K,
Smith A.
Nanomedicine targeting PPAR in adipose tissue macrophages improves lipid metabolism and obesity-induced metabolic dysfunction. Sci Adv. 2025;11(39):eads3731
Keywords
JGM, Animals, Obesity, Macrophages, Adipose Tissue, Nanomedicine, Lipid Metabolism, Mice, Male, Female, Peroxisome Proliferator-Activated Receptors, Disease Models, Animal
JAX Source
Sci Adv. 2025;11(39):eads3731
ISSN
2375-2548
PMID
41004576
DOI
https://doi.org/10.1126/sciadv.ads3731
Abstract
Excess body fat leads to an overabundance of adipose tissue macrophages (AT MΦs) with altered phenotypes that play pathogenic roles in obesity comorbidities including diabetes and cancer. Peroxisome proliferator-activated receptors (PPARs) are leading targets to modulate AT MΦ phenotype. Here, we developed a dextran-based nanomedicine that delivers PPARα/γ agonists to AT MΦs and improves obesity and diabetic phenotypes in vivo. Within 1 week of treatment, AT MΦs decreased and became lipid laden, while extracellular vesicles secreted from AT decreased and reduced in lipid content. Within 2 weeks, glucose tolerance returned to levels of lean controls, followed by weight loss and reduced food intake. After 4 weeks, AT browning and amelioration of hepatic steatosis were evident. The physiological shifts were reproducible in three rodent models of obesity, spanning sexes and gonadal status. Effects were enhanced for the targeted nanomedicine compared with free drugs at equivalent doses, supporting the hypothesis that targeted PPAR activation in AT MΦs benefits systemic metabolism.
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