High-fat diet-induced acceleration of osteoarthritis is associated with a distinct and sustained plasma metabolite signature

Abstract

Metabolic changes induced by high fat diet (HFD) that contribute to osteoarthritis (OA) are poorly understood. We investigated longitudinal changes to metabolites and their contribution to OA pathogenesis in response to HFD. HFD-fed mice exhibited acceleration of spontaneous age-related and surgically-induced OA compared to lean diet (LD)-fed mice. Using metabolomics, we identified that HFD-fed mice exhibited a distinct and sustained plasma metabolite signature rich in phosphatidylcholines (PC) and lysophosphatidylcholines (lysoPCs), even after resumption of normal chow diet. Using receiver operator curve analysis and prediction modelling, we showed that the concentration of these identified metabolites could efficiently predict the type of diet and OA risk with an accuracy of 93%. Further, longitudinal evaluation of knee joints of HFD- compared to LD- fed mice showed a greater percentage of leptin-positive chondrocytes. Mechanistic data showed that leptin-treated human OA chondrocytes exhibited enhanced production of lysoPCs and expression of autotaxin and catabolic MMP-13. Leptin-induced increased MMP13 expression was reversed by autotaxin inhibition. Together, this study is the first to describe a distinct and sustained HFD-induced metabolite signature. This study suggests that in addition to increased weight, identified metabolites and local leptin-signaling may also contribute in part, towards the accelerated OA-phenotype observed in HFD mice.

Interaction of Osteoarthritis and BMI on Leptin Promoter Methylation in Taiwanese Adults

“…As previously stated, the incidence of osteoarthritis in obese individuals is high [32]. Our findings suggest that LEP methylation might be involved in the pathogenesis of osteoarthritis.…”

“…Most studies have demonstrated that serum leptin levels in people with osteoarthritis are high [10,15,32]. In our study, LEP promoter methylation levels were higher in obese individuals with osteoarthritis.…”

Shea Nut Oil Extracts Enhance the Intra-Articular Sodium Hyaluronate Effectiveness on Surgically Induced OA Progression in Rats

“…Mooney et al showed that surgically-induced OA mice fed a high-fat diet presented not only higher fasting glucose levels and body weights compared to those of lean OA mice, but also had worse OARSI histological scores and less cartilage thickness [40]. Moreover, a recent report also demonstrated that cartilage deterioration was sustained even after the high-fat diet was withdrawn from the OA mice, and the blood glucose and body weight were restored to the levels in normal diet mice [41]. These findings suggested that an increased weight load is not the sole cause of the severity of OA progression; instead, the lipid/glucose metabolic pathways could also jeopardize cartilage integrity and synthesis.…”

Noninvasive visualization of early osteoarthritic cartilage using targeted nanosomes in a destabilization of the medial meniscus mouse model

“…At each week of the time interval, animals were anesthetized with 2.5% isoflurane 24 hours after injection of the final probe and scanned by IVIS imaging to determine fluorescent binding in the knee joint. The fluorescence from the knee joint was quantified by the Living Image software to calculate the flux radiating omnidirectionally from the ROI and graphed as radiant efficiency ([photons/second/cm 2 /str]/[μW/cm 2 ]). To determine an average ROI from the knee fluorescence, the same area of capture was used for each mouse.…”

“…1 OA is a manifestation of obesity, aging, trauma, and mechanical stress. 2,3 It typically appears in weight-bearing joints as focal lesions that progressively deepen until the subchondral bone is exposed. 4,5 Although focal lesions in the cartilage can be repaired, no appropriate treatment has been developed to reverse cartilage degradation.…”