Abstract

Obesogenic diets contribute to the pathology of osteoarthritis (OA) by altering systemic and local metabolic inflammation. Yet, it remains unclear how quickly and reproducibly the body responds to weight loss strategies and improve OA. In this study we tested whether switching obese diet to a normal chow diet can mitigate the detrimental effects of inflammatory pathways that contribute to OA pathology. Male C57BL/6 mice were first fed with obesogenic diet (high fat diet) and switched to normal chow diet (obese diet → normal diet) or continued obese diet or normal diet throughout the experiment. A mouse model of OA was induced by surgical destabilization of the medial meniscus (DMM) model into the knee joint. Outcome measures included changes in metabolic factors such as glucose, insulin, lipid, and serum cytokines levels. Inflammation in synovial biopsies was scored and inflammation was determined using FACs sorted macrophages. Cartilage degeneration was monitored using histopathology. Our results indicate, dietary switching (obese diet → normal diet) reduced body weight and restored metabolic parameters and showed less synovial tissue inflammation. Systemic blood concentrations of pro-inflammatory cytokines IL-1α, IL-6, IL-12p40, and IL-17 were decreased, and anti-inflammatory cytokines IL-4 and IL-13 were increased in dietary switch group compared to mice that were fed with obesogenic diet continuously. Although obese diet worsens the cartilage degeneration in DMM OA model, weight loss induced by dietary switch does not promote the histopathological changes of OA during this study period. Collectively, these data demonstrate that switching obesogenic diet to normal improved metabolic syndrome symptoms and can modulate both systemic and synovium inflammation levels.

Highlights

  • Obesity and its associated metabolic disorders are an important contributor to the progression of OA [1,2,3,4,5]

  • Following weight loss of the HFD∼CD group, serum insulin, TG, cholesterol, and low-density lipoprotein (LDL) concentrations were decreased, and high-density lipoprotein (HDL) concentrations were increased as compared to HFDmice (Figures 1D–H)

  • We report 4 key findings: [1] obesogenic diets lead to OA changes in the knee joint in C57BL/6J mice; [2] obesogenic diets induce an accumulation of pro-inflammatory macrophages in the synovium and fat pad tissues; [3] replacement of the obesogenic diet with a control diet decreased systemic metabolic syndrome symptoms, circulating concentrations of inflammatory cytokines and inflammatory signaling activities; and [4] replacement of obesogenic diets with a control diet somewhat reduced synovial pro-inflammatory gene expression, and mitigated the effects of obesity-associated OA development

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Summary

Introduction

Obesity and its associated metabolic disorders are an important contributor to the progression of OA [1,2,3,4,5]. The underlying mechanisms that link OA with obesity remain to be elucidated, the state of chronic low-grade inflammation in obesity, which is caused by an increased accumulation of macrophages in the adipose tissue, has been proposed [7]. There was an inverse dose-response relationship between weight loss and progression of cartilage abnormalities in obese patients with knee OA [12, 13]. Weight loss has been extensively studied regarding its short-term benefits on major symptoms in obese patients with chronic diseases including OA [13, 14], the effect of weight loss on the progression of morphologic abnormalities of the knee joints remains a key area of ongoing research

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