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

Abstract

Objective To test the hypothesis that high-fat (HF) diet-induced obesity increases pro-inflammatory 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 epididymal, subcutaneous, and infrapatellar fat pads and adipocyte sizes. Finally, we utilized targeted gene expression and protein arrays, immunohistochemsitry, and flow cytometry to quantify differences in fat pad inflammatory markers and immune cell populations. Results 20 weeks of HF diet treatment induced marked obesity, glucose intolerance, and early osteoarthritis (OA), including osteophytes and cartilage tidemark duplication. This duration of HF feeding increased IFP volume. However, it did not increase IFP inflammation, macrophage infiltration, or M1 macrophage polarization as observed in epididymal fat. Furthermore, leptin protein was reduced. This protection from obesity-induced inflammation corresponded with increased IFP fibrosis and the absence of adipocyte hypertrophy. Conclusion The IFP does not recapitulate classical abdominal adipose tissue inflammation during the early stages of knee OA in a high-fat 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 pro-fibrotic and anti-hypertrophic responses of IFP adipocytes to high-fat feeding suggest that intra-articular adipocytes are subject to distinct spatial-temporal structural and metabolic regulation among fat pads.

TLR4 Promotes and DAP12 Limits Obesity‐Induced Osteoarthritis in Aged Female Mice

“…For mice, this is roughly equivalent to an accelerated onset of OA by 3 to 4 months compared with that observed in a 20‐month‐old animal. In general, when OA is initiated in mice via high‐fat diet‐ (HFD‐) induced obesity without an additional injury, diet durations of 9 to 12 months are required to increase the disease severity . Interestingly, a small reduction in body weight (5 kg), and in particular body fat (2.4%), slows the progression of OA, supporting a role for metabolic factors .…”

“…In general, when OA is initiated in mice via high-fat diet-(HFD-) induced obesity without an additional injury, diet durations of 9 to 12 months are required to increase the disease severity. (4,5) Interestingly, a small reduction in body weight (5 kg), and in particular body fat (2.4%), slows the progression of OA, supporting a role for metabolic factors. (6,7) The molecular pathways directly linking obesity-induced systemic or local joint inflammation to cartilage catabolism and OA progression are still unknown, but the dysfunction of innate immune responses may be a link.…”

Adipose Tissue is a Critical Regulator of Osteoarthritis

“…IL-4 is another promising anti-inflammatory candidate for cartilage protection under active investigation, and here we observed increased IL-4 in LD mice (39). However, as IL-4 can also induce TARC/CCL-17 via STAT6, there may be off- with several studies that demonstrate increased body mass per se does not explain obesity-associated knee OA, but that in fact, associations with systemic pro-inflammatory mediators and other tissues (e.g., muscle) provide robust associations with OA pathogenesis (1, 5,7,8,24,28), which is the opposite of what we observed in the LD mice. As such, we postulate that the strong anti-inflammatory signature evidenced in LD mice, which is reversed upon adipose implantation, is a key driver of this protection, and that systemic overexpression of antiinflammatory mediators may be a useful therapeutic approach for chondroprotection with injury or obesity.…”

“…Notably, while LD mice lack adipose tissue, which is thought to serve as a local source of proinflammatory mediators and adipokines within articulating joints (23,24). LD mice exhibited several characteristics traditionally thought to contribute to the onset and progression of cartilage damage associated with obesity.…”

“…Adipose tissue could drive OA susceptibility directly through adipokines, through changes in systemic inflammation that ultimately manifest locally within the joint, or indirectly through another signaling axis absent in LD mice. In this regard, leptin is the most consistently increased mediator reported in obesity-induced OA (7,8,24,28) and can drive OA-associated inflammation (28). Obesity is associated with increased circulating levels of leptin thought to arise in response to leptin resistance (3).…”