Effects of Leptin and Body Weight on Inflammation and Knee Osteoarthritis Phenotypes in Female Rats
ABSTRACT Leptin is a proinflammatory adipokine that contributes to obesity‐associated osteoarthritis (OA), especially in women. However, the extent to which leptin causes knee OA separate from the effect of increased body weight is not clear. We hypothesized that leptin is necessary to induce knee O...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Oxford University Press
2023-07-01
|
| Series: | JBMR Plus |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jbm4.10754 |
| _version_ | 1827199534247182336 |
|---|---|
| author | Yao Fu Albert Batushansky Michael Kinter Janet L. Huebner Virginia B. Kraus Timothy M. Griffin |
| author_facet | Yao Fu Albert Batushansky Michael Kinter Janet L. Huebner Virginia B. Kraus Timothy M. Griffin |
| author_sort | Yao Fu |
| collection | DOAJ |
| description | ABSTRACT Leptin is a proinflammatory adipokine that contributes to obesity‐associated osteoarthritis (OA), especially in women. However, the extent to which leptin causes knee OA separate from the effect of increased body weight is not clear. We hypothesized that leptin is necessary to induce knee OA in obese female rats but not sufficient to induce knee OA in lean rats lacking systemic metabolic inflammation. The effect of obesity without leptin signaling was modeled by comparing female lean Zucker rats to pair fed obese Zucker rats, which possess mutant fa alleles of the leptin receptor gene. The effect of leptin without obesity was modeled in female F344BN F1 hybrid rats by systemically administering recombinant rat leptin versus saline for 23 weeks via osmotic pumps. Primary OA outcomes included cartilage histopathology and subchondral bone micro‐computed tomography. Secondary outcomes included targeted cartilage proteomics, serum inflammation, and synovial fluid inflammation following an acute intra‐articular challenge with interleukin‐1β (IL‐1β). Compared to lean Zucker rats, obese Zucker rats developed more severe tibial osteophytes and focal cartilage lesions in the medial tibial plateau, with modest changes in proximal tibial epiphysis trabecular bone structure. In contrast, exogenous leptin treatment, which increased plasma leptin sixfold without altering body weight, caused mild generalized cartilage fibrillation and reduced Safranin O staining compared to vehicle‐treated animals. Leptin also significantly increased subchondral and trabecular bone volume and bone mineral density in the proximal tibia. Cartilage metabolic and antioxidant enzyme protein levels were substantially elevated with leptin deficiency and minimally suppressed with leptin treatment. In contrast, leptin treatment induced greater changes in systemic and local inflammatory mediators compared to leptin receptor deficiency, including reduced serum IL‐6 and increased synovial fluid IL‐1β. In conclusion, rat models that separately elevate leptin or body weight develop distinct OA‐associated phenotypes, revealing how obesity increases OA pathology through both leptin‐dependent and independent pathways. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. |
| first_indexed | 2024-03-13T00:02:09Z |
| format | Article |
| id | doaj.art-aa1cc937840a407a886dca46ed902848 |
| institution | Directory Open Access Journal |
| issn | 2473-4039 |
| language | English |
| last_indexed | 2025-03-21T10:34:26Z |
| publishDate | 2023-07-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | JBMR Plus |
| spelling | doaj.art-aa1cc937840a407a886dca46ed9028482024-07-02T22:08:09ZengOxford University PressJBMR Plus2473-40392023-07-0177n/an/a10.1002/jbm4.10754Effects of Leptin and Body Weight on Inflammation and Knee Osteoarthritis Phenotypes in Female RatsYao Fu0Albert Batushansky1Michael Kinter2Janet L. Huebner3Virginia B. Kraus4Timothy M. Griffin5Aging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City Oklahoma USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City Oklahoma USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City Oklahoma USADuke Molecular Physiology Institute Duke University, School of Medicine, Duke University Durham North Carolina USADuke Molecular Physiology Institute Duke University, School of Medicine, Duke University Durham North Carolina USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City Oklahoma USAABSTRACT Leptin is a proinflammatory adipokine that contributes to obesity‐associated osteoarthritis (OA), especially in women. However, the extent to which leptin causes knee OA separate from the effect of increased body weight is not clear. We hypothesized that leptin is necessary to induce knee OA in obese female rats but not sufficient to induce knee OA in lean rats lacking systemic metabolic inflammation. The effect of obesity without leptin signaling was modeled by comparing female lean Zucker rats to pair fed obese Zucker rats, which possess mutant fa alleles of the leptin receptor gene. The effect of leptin without obesity was modeled in female F344BN F1 hybrid rats by systemically administering recombinant rat leptin versus saline for 23 weeks via osmotic pumps. Primary OA outcomes included cartilage histopathology and subchondral bone micro‐computed tomography. Secondary outcomes included targeted cartilage proteomics, serum inflammation, and synovial fluid inflammation following an acute intra‐articular challenge with interleukin‐1β (IL‐1β). Compared to lean Zucker rats, obese Zucker rats developed more severe tibial osteophytes and focal cartilage lesions in the medial tibial plateau, with modest changes in proximal tibial epiphysis trabecular bone structure. In contrast, exogenous leptin treatment, which increased plasma leptin sixfold without altering body weight, caused mild generalized cartilage fibrillation and reduced Safranin O staining compared to vehicle‐treated animals. Leptin also significantly increased subchondral and trabecular bone volume and bone mineral density in the proximal tibia. Cartilage metabolic and antioxidant enzyme protein levels were substantially elevated with leptin deficiency and minimally suppressed with leptin treatment. In contrast, leptin treatment induced greater changes in systemic and local inflammatory mediators compared to leptin receptor deficiency, including reduced serum IL‐6 and increased synovial fluid IL‐1β. In conclusion, rat models that separately elevate leptin or body weight develop distinct OA‐associated phenotypes, revealing how obesity increases OA pathology through both leptin‐dependent and independent pathways. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.https://doi.org/10.1002/jbm4.10754ADIPOKINESKNEEMETABOLIC SYNDROMEMETABOLISMOBESITYOSTEOARTHRITIS |
| spellingShingle | Yao Fu Albert Batushansky Michael Kinter Janet L. Huebner Virginia B. Kraus Timothy M. Griffin Effects of Leptin and Body Weight on Inflammation and Knee Osteoarthritis Phenotypes in Female Rats JBMR Plus ADIPOKINES KNEE METABOLIC SYNDROME METABOLISM OBESITY OSTEOARTHRITIS |
| title | Effects of Leptin and Body Weight on Inflammation and Knee Osteoarthritis Phenotypes in Female Rats |
| title_full | Effects of Leptin and Body Weight on Inflammation and Knee Osteoarthritis Phenotypes in Female Rats |
| title_fullStr | Effects of Leptin and Body Weight on Inflammation and Knee Osteoarthritis Phenotypes in Female Rats |
| title_full_unstemmed | Effects of Leptin and Body Weight on Inflammation and Knee Osteoarthritis Phenotypes in Female Rats |
| title_short | Effects of Leptin and Body Weight on Inflammation and Knee Osteoarthritis Phenotypes in Female Rats |
| title_sort | effects of leptin and body weight on inflammation and knee osteoarthritis phenotypes in female rats |
| topic | ADIPOKINES KNEE METABOLIC SYNDROME METABOLISM OBESITY OSTEOARTHRITIS |
| url | https://doi.org/10.1002/jbm4.10754 |
| work_keys_str_mv | AT yaofu effectsofleptinandbodyweightoninflammationandkneeosteoarthritisphenotypesinfemalerats AT albertbatushansky effectsofleptinandbodyweightoninflammationandkneeosteoarthritisphenotypesinfemalerats AT michaelkinter effectsofleptinandbodyweightoninflammationandkneeosteoarthritisphenotypesinfemalerats AT janetlhuebner effectsofleptinandbodyweightoninflammationandkneeosteoarthritisphenotypesinfemalerats AT virginiabkraus effectsofleptinandbodyweightoninflammationandkneeosteoarthritisphenotypesinfemalerats AT timothymgriffin effectsofleptinandbodyweightoninflammationandkneeosteoarthritisphenotypesinfemalerats |