In a new study published in Scientific Reports, researchers have uncovered the molecular mechanism underlying the link between obesity and joint degeneration .
Obesity and osteoarthritis
Obesity accelerates aging and is associated with several age-associated diseases, including osteoarthritis, an inflammatory condition that leads to joint degeneration. Obesity is often accompanied by low-grade chronic inflammation, which might exacerbate joint damage.
Remarkably, 60% of osteoarthritis cases are estimated to be obesity-related and are categorized as metabolic osteoarthritis. Although the connection between obesity and osteoarthritis is evident, the underlying molecular mechanism is unclear.
It was previously shown that increased fat (adipose) tissue is associated with an increased level of adipokines: inflammatory signaling molecules that are secreted by fat cells (adipocytes), such as resistin. Patients with osteoarthritis have high levels of resistin, which induces the expression of enzymes that degrade the extracellular matrix and thus cartilage.
In this study, the researchers sought to investigate the connection between obesity and osteoarthritis and whether it’s mediated by resistin. They also looked into dysregulated autophagy as a possible link between the two conditions.
Molecular changes in obese rats
The experiments were performed on thirty 2-3 month old male rats that were following either a normal diet (control) or a high-fat diet for 12 weeks. Following physical parameter measurements, the mice were sacrificed and their tissues were collected for analysis.
First, unsurprisingly, the rats on the high-fat diet were shown to increase in both BMI and body weight by ~70% compared to controls: they became obese. The rats on the high-fat diet also demonstrated elevated levels of sugar, insulin, triglycerides, and total and LDL cholesterol, along with a reduced level of HDL cholesterol.
Next, the researchers showed that the levels of resistin and TLR4, a target of resistin that triggers cytokine production, is higher in the obese rats compared to controls. Consistently with that, the levels of osteoarthritis markers, such as IL-1β, caspase-3, and MMP-9, were all elevated in the rats on the high fat diet.
An increased expression level of autophagy markers, Beclin-1, LC3B and ATG5, and a decrease of mTOR expression were detected in the obese rats, suggesting increased autophagy caused by the high-fat diet. This is somewhat in contrast with previous reports demonstrating repressed autophagy with osteoarthritis progression. On the other hand, an early phase of the cartilage degenerative process might be accompanied by induced autophagy, which serves as a protective response to damage.
Statistical analysis confirmed a positive correlation between resistin, TLR4, some matrix-degrading enzymes, and autophagy markers. The researchers conclude that, based on this finding, TLR4 could be a direct receptor of resistin in the cartilage triggering the degradation process.
Tissue degradation in obese rats
Finally, the researchers assessed the morphological characteristics of the knee cartilage in obese and control rats. Several structural abnormalities were detected in the tissues of rats on a high-fat diet, which resulted in the cartilage thinning.
Obesity is a significant risk factor for the development of knee osteoarthritis (KOA). However, the precise molecular mechanisms linking obesity to OA remain unclear. In the present study, we investigated the effect of short-term high-fat diet (HFD) on the development of OA and the possible role of the adipokine resistin and autophagy-related genes in mediating this effect. Thirty adult male Wistar rats were equally divided into 2 groups: control and obese groups. Body mass index (BMI), levels of lipid profile, glucose, insulin and HOMA-IR index were significantly higher in the obese group compared with control. Our results revealed significantly higher serum and cartilage resistin levels with a significant increase in the mRNA expressions of toll-like receptor 4 (TLR4), matrix metalloproteinase-9 (MMP-9) and interleukin-1β (IL-1β) as well as protein levels of IL-1β, matrix metalloproteinase-13 (MMP-13), ADAMTS 5 (aggrecanase-2) and caspase-3 in the cartilage of obese rats. The HFD induced a significant upregulation of autophagy related 5 (ATG5), beclin-1 and light chain 3 (LC3) mRNA expressions and a significant downregulation of mammalian target of rapamycin (mTOR) expression in cartilage. The protein levels of cartilage ATG5 were also significantly elevated in HFD-fed group. In conclusion, we suggested that increased levels of resistin and expression of autophagy-related genes may contribute in part, to OA development in HFD-fed rats. This provides a novel insight into the early molecular changes in the cartilage associated with obesity.
This study sheds light on the molecular mechanisms underlying the connection between obesity and osteoarthritis. High-fat diet-caused obesity increases the level of inflammatory molecules and matrix-degrading enzymes via upregulating resistin. This, in turn, triggers the cartilage degradation process, which is accompanied by elevated autophagy. As we can see in rats, even a short-term high-fat diet in otherwise healthy animals is detrimental to their joint health. This study is another reminder of the deleterious effects of a Western diet and a call to switch to a well-balanced diet.
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 Aboudeya, H. M., Shaker, S. A. & Salama, M. Effect of short-term high fat diet on resistin levels and expression of autophagy-related genes in the cartilage of male rats. Sci. Rep. 12, 15313 (2022)