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  3. Nanomedicine targeting PPAR in adipose tissue macrophages improves lipid metabolism and obesity-induced metabolic dysfunction

Nanomedicine targeting PPAR in adipose tissue macrophages improves lipid metabolism and obesity-induced metabolic dysfunction

  • Sci Adv. 2025 Sep 26;11(39):eads3731. doi: 10.1126/sciadv.ads3731.
Catherine C Applegate 1 2 3,  Yifei Kang 4,  Hongping Deng 2 5,  Donglai Chen 6,  Natalia Y Gonzalez Medina 2,  Yuxiao Cui 2 5,  Yujun Feng 6,  Chia-Wei Kuo 2 5,  Sayyed Hamed Shahoei 7 8,  Hannah Kim 7,  Hashni Epa Vidana Gamage 7,  Matthew A Wallig 9 10,  Erik R Nelson 4 7 11 12,  Kelly S Swanson 1 4 10,  Andrew M Smith 2 4 5 6 11 12 13
Affiliations

Affiliations

  • 1 Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
  • 2 Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
  • 3 The Beckman Institute of Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
  • 4 Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
  • 5 Micro and Nanotechnology Laboratory, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
  • 6 Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • 7 Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
  • 8 The Jackson Laboratory, Farmington, CT 06032, USA.
  • 9 Department of Pathobiology, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
  • 10 Department of Veterinary Clinical Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
  • 11 Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
  • 12 Carl R. Woese Institute for Genomic Biology, Anticancer Discovery from Pets to People Theme, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
  • 13 Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
PMID: 41004576 DOI: 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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