Profibrotic Infrapatellar Fat Pad Remodeling Without M1 Macrophage Polarization Precedes Knee Osteoarthritis in Mice With Diet‐Induced Obesity

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Abstract
Objective: To test the hypothesis that high‐fat (HF) diet–induced obesity increases proinflammatory cytokine expression, macrophage infiltration, and M1 polarization in the infrapatellar fat pad (IFP) prior to knee cartilage degeneration.Methods: We characterized the effect of HF feeding on knee OA pathology, body adiposity, and glucose intolerance in male C57BL/6J mice and identified a diet duration that induces metabolic dysfunction prior to cartilage degeneration. Magnetic resonance imaging and histomorphology were used to quantify changes in the epididymal, subcutaneous, and infrapatellar fat pads and in adipocyte sizes. Finally, we used targeted gene expression and protein arrays, immunohistochemistry, and flow cytometry to quantify differences in fat pad markers of inflammation and immune cell populations.Results: Twenty weeks of feeding with an HF diet induced marked obesity, glucose intolerance, and early osteoarthritis (OA), including osteophytes and cartilage tidemark duplication. This duration of HF feeding increased the IFP volume. However, it did not increase IFP inflammation, macrophage infiltration, or M1 macrophage polarization as observed in epididymal fat. Furthermore, leptin protein levels were reduced. This protection from obesity‐induced inflammation corresponded to increased IFP fibrosis and the absence of adipocyte hypertrophy.Conclusion: The IFP does not recapitulate classic abdominal adipose tissue inflammation during the early stages of knee OA in an HF diet–induced model of obesity. Consequently, these findings do not support the hypothesis that IFP inflammation is an initiating factor of obesity‐induced knee OA. Furthermore, the profibrotic and antihypertrophic responses of IFP adipocytes to HF feeding suggest that intraarticular adipocytes are subject to distinct spatiotemporal structural and metabolic regulation among fat pads.
Funding Information
  • National Institutes of Health
  • National Center for Research Resources (P20‐RR‐018758)
  • National Institute of General Medical Sciences (P20‐GM‐103441)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R03‐AR‐066828)
  • Arthritis Foundation

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