Acquired leptin resistance by high-fat feeding reduces inflammation induced by collagen antibody induced arthritis (CAIA) in mice

INTRODUCTION: Leptin is a peptide hormone secreted by adipocytes which regulates body weight and food intake. Serum leptin concentration is increased in obesity and is strongly correlated with total body fat mass. Also leptin was reported to be necessary in T-helper 1 (Th1) dependent inflammatory processes [1]. Severity of antigen-induced arthritis in leptin-deficient ob/ob mice was reduced [2].Clinically, rheumatoid arthritis (RA) patients with high body mass index (BMI) have lower disease activity compared to thinner patients [3]. These results are paradoxical findings in leptin efficacy in immune systems. In the previous studies, it has been suggested that most obesity have resistance to the anorectic and weight-reducing effects of leptin. It is uncertain whether any role that leptin may play in leptin resistance obesity is linked to changes in the immune system. Consequently, we have adopted high fat diet-induced obese mice which acquired leptin resistance as a means of examining the underlying causes of human obesity. And then we examined the effects of leptin resistance on collagen antibody induced arthritis (CAIA) in these model mice. METHODS: Diet therapies were induced in C57BL/6J mice (4 weeks old, female) by exposure to 50% fat to obesity and 11.5% fat to normal for 6 weeks. We examined serum leptin concentration and peripheral or central leptin response to confirm the development of leptin resistance. A cocktail of arthritogenic monoclonal antibodies to type II collagen (CAIA Chondrex, Redmond, CA) (day1 and 1) combined with a boost of LPS (day3) is used to induced CAIA. Leptin injections were started day 2 continued for 6 days by intraperitoneally (ip) or intracerebroventicular (ICV). The animals were sacrificed at day 11. Daily assessment of four paws swelling was used to monitor the development of arthritis according to Terato criteria [4]. The histopathologic features were also analyzed by Toluidine blue. RESULTS: Mice fed a high-fat diet (obese) had a significantly higher body weight in comparison to mice fed the control diet (control) from week 2 onwards until 6 weeks (Fig 1). After feeding period, serum leptin concentrations were about four times higher in obese mice (mean 430ng/ml) than control mice (111ng/ml). The simple linear regression analyses of obese group indicated that serum leptin levels correlated positively with body weight (Fig2).