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Body weight is a component of the mechanical theory of OA (osteoarthritis) pathogenesis. Obesity was also found to be a risk factor for digital OA involving non-weight-bearing joints, which suggested that metabolism influences the occurrence and progression of OA. The metabolic origin of OA has been partially attributed to the involvement of adipokines, such as leptin, the levels of which are significantly and positively correlated with cartilage degeneration in OA patients. However, the mechanisms by which leptin-induced cartilage degeneration occurs are poorly understood. The discovery of chondrogenic progenitor cells (CPCs) opened up new opportunities for investigation. Investigating the effects of leptin on differentiation and proliferation in CPCs would increase our understanding of the roles played by leptin in the aetiology and development of OA. Here, CPCs were harvested using single-cell sorting from rat cartilage tissues to obtain mesenchymal stem-like cells, which possess clonogenicity, proliferation and stemness. High doses of leptin decreased the ability of the CPCs to migrate, inhibited their chondrogenic potential and increased their osteogenic potential, suggesting that leptin changes differentiation fates in CPCs. High doses of leptin induced cell cycle arrest and senescence in CPCs by activating the p53/p21 pathway and inhibiting the Sirt1 pathway. Inhibiting the Sirt1 pathway accelerated cartilage senescence in knockout (KO) mice. Activating the leptin pathway induced higher Ob-Rb expression and was significantly correlated with cartilage degeneration (lower levels of Coll-2) and tissue senescence (higher levels of p53/p21 and lower levels of Sirt1) in OA patients, suggesting that leptin-induced CPCs senescence contributes to the development of OA. Taken together, our results reveal new links between obesity and cartilage damage that are induced by leptin-mediated effects on cell behaviour and senescence.

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OBJECTIVETo evaluate the association of body size and fat distribution with risk of colorectal cancer (CRC) in Chinese men and women.DESIGNPopulation-based, prospective cohort study.SUBJECTSThe analysis included 134 255 Chinese adults enrolled in the Shanghai Women’s Health Study and the Shanghai Men’s Health Study, with an average follow-up of 11.0 and 5.5 years, respectively.MEASUREMENTSWaist circumference (WC), body mass index (BMI) and waist-to-hip ratio (WHR) were measured by trained interviewers at baseline. Multivariable Cox models were used to calculate adjusted hazard ratios (HRs) for incident CRC.RESULTSA total of 935 incident CRC cases were identified. Both measures of general adiposity (measured by BMI) and central adiposity (measured by WHR and WC) were significantly associated with increased risk of colon cancer in men but not in women. Multivariable adjusted HRs for colon cancer in men in the highest compared with the lowest quintiles were 2.15 (95% CI: 1.35-3.43; P for trend = 0.0006) for BMI, 1.97 (95% CI: 1.19-3.24; P for trend = 0.0004) for WHR and 2.00 (95% CI: 1.21-3.29; P for trend = 0.0002) for WC. The BMI-associated risk was attenuated in analyses stratified by WHR, while the WHR-associated risk remained significant in the high BMI stratum (HR for comparison of extreme tertiles of WHR: 3.38, 95% CI: 1.47-7.75; P for trend =0.0002). None of these anthropometric measures were significantly associated with rectal cancer.CONCLUSIONObesity, particularly central obesity, was associated with increased risk of colon cancer in men.