Acquired leptin resistance by high-fat feeding reduces inflammation from collagen antibody-induced arthritis in mice.
OBJECTIVE
Rheumatoid arthritis (RA) patients with high body mass index (BMI) show lower mortality than thinner patients, indicating a paradoxical effect of body mass on mortality in RA. We considered that leptin might play some part in this mechanism. Leptin regulates not only body weight, but also inflammatory processes. Furthermore, hyperleptinemia decreases sensitivity to leptin (leptin resistance). This study examined whether high-fat diet-induced hyperleptinemic obese mice with acquired leptin resistance show reduced inflammation induced by collagen antibody-induced arthritis (CAIA).


METHODS
Diet therapies were induced in mice by exposure to 50% fat to obesity for 6 weeks. We examined serum leptin concentrations and leptin responses after 6 weeks and induced CAIA. Leptin effects were examined by intraperitoneal (IP) or intracerebroventricular (ICV) leptin administration after CAIA. Hindpaw swelling was monitored daily. Histopathological features were also determined at sacrifice.


RESULTS
Serum leptin concentrations were approximately 5-fold higher than in normal mice. IP leptin did not inhibit food intake, but ICV leptin did. Obese mice thus acquired peripheral leptin resistance. Arthritis was reduced approximately 30% compared with normal controls and was not exacerbated by IP leptin injection, but ICV leptin injection exacerbated arthritis to levels equal to normal controls. Histopathological assessment showed that cartilage damage was reduced by 76% compared to normal controls.


CONCLUSIONS
High-fat diet-induced obese mice acquired peripheral leptin resistance reducing the development of CAIA. Leptin sensitivity was associated with severity of arthritis. These results suggest that RA patients with high BMI who acquire leptin resistance may show reduced inflammation. However, the real function of leptin in the immune system remains partly unclear.
Department of Orthopaedic Surgery, Osaka City University Medical School, Osaka, Japan. ysugioka@med.osaka-cu.ac.jp
Yuko
Y
Sugioka
Masahiro
M
Tada
Tadashi
T
Okano
Hiroaki
H
Nakamura
Tatsuya
T
Koike
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001169:Arthritis, Experimental / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001835:Body Weight; D024043:Collagen Type II / Q000276:immunology*; D059305:Diet, High-Fat; D005260:Female; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007596:Joints / Q000473:pathology; D020738:Leptin / Q000008:administration & dosage / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood* / Q000276:immunology; D012720:Severity of Illness Index; D013997:Time Factors; D015854:Up-Regulation
D000906:Antibodies; D024043:Collagen Type II; D020738:Leptin