title: Toward understanding the role of leptin and leptin receptor antagonism in preclinical models of rheumatoid arthritis.
abstract: A potential link between obesity, circulating leptin levels and autoimmune disease symptoms suggests that targeting the leptin receptor (ObR) might be a viable novel strategy to combat rheumatoid arthritis (RA). However, studies in animal models and evaluation of clinical cases did not provide clear view on leptin's involvement in RA. To validate ObR as RA target, we used our peptide-based ObR agonists and antagonist in different in vitro and in vivo models of the disease. In human peripheral blood mononuclear cells, leptin and its agonist fragment, desI(2)-E1/Aca, moderately induced constitutive activation of a major proinflammatory transcription factor, NF-κB, while the ObR antagonist peptide Allo-aca inhibited the process. Leptin administration itself did not induce arthritis in rats, but worsened the clinical condition of mice given K/BxN serum transfer arthritis. Simultaneous administration of Allo-aca reduced leptin-dependent increase in disease severity by more than 50%, but the antagonist was ineffective when injected with a 3-day delay. In rats inflicted with mild adjuvant-induced arthritis, both leptin and Allo-aca reduced the extent of joint swelling and the number of arthritic joints. In a more aggressive disease stage, Allo-aca decreased the number of arthritic joints in a dose-dependent manner but did not affect other arthritis markers. In summary, leptin exerts diverse effects on RA depending on the experimental model. This might reflect the heterogeneous character of RA, which is differently impacted by leptin and is unmasked by ObR antagonism. Nevertheless, the results suggest that ObR antagonists might become useful therapeutics in leptin-sensitive early stages of RA.
authors: Department of Biology, Temple University, Philadelphia, PA 19122, USA. lotvos@comcast.net
authors: Laszlo
authors: L
authors: Otvos
authors: Wen-Hai
authors: WH
authors: Shao
authors: Anne S
authors: AS
authors: Vanniasinghe
authors: Michael A
authors: MA
authors: Amon
authors: Marianna Csilla
authors: MC
authors: Holub
authors: Ilona
authors: I
authors: Kovalszky
authors: John D
authors: JD
authors: Wade
authors: Michelle
authors: M
authors: Doll
authors: Philip L
authors: PL
authors: Cohen
authors: Nicholas
authors: N
authors: Manolios
authors: Eva
authors: E
authors: Surmacz
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020738:Leptin / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020738:Leptin; D009842:Oligopeptides; D054411:Receptors, Leptin; C562042:threonyl-glutamyl-norvalyl-alanyl-leucyl-leucyl-seryl-arginyl-aminocaproamide