Cysteine cathepsin S processes leptin, inactivating its biological activity.
Leptin is a 16  kDa hormone mainly produced by adipocytes that plays an important role in many biological events including the regulation of appetite and energy balance, atherosclerosis, osteogenesis, angiogenesis, the immune response, and inflammation. The search for proteolytic enzymes capable of processing leptin prompted us to investigate the action of cysteine cathepsins on human leptin degradation. In this study, we observed high cysteine peptidase expression and hydrolytic activity in white adipose tissue (WAT), which was capable of degrading leptin. Considering these results, we investigated whether recombinant human cysteine cathepsins B, K, L, and S were able to degrade human leptin. Mass spectrometry analysis revealed that among the tested enzymes, cathepsin S exhibited the highest catalytic activity on leptin. Furthermore, using a Matrigel assay, we observed that the leptin fragments generated by cathepsin S digestion did not exhibit angiogenic action on endothelial cells and were unable to inhibit food intake in Wistar rats after intracerebroventricular administration. Taken together, these results suggest that cysteine cathepsins may be putative leptin activity regulators in WAT.
Departamento de Biofísica, Universidade Federal de São Paulo, Rua Pedro de Toledo 669, São Paulo, São Paulo 04039-032, Brazil.
Marcela
M
Oliveira
Diego M
DM
Assis
Thaysa
T
Paschoalin
Antonio
A
Miranda
Eliane B
EB
Ribeiro
Maria A
MA
Juliano
Dieter
D
Brömme
Marcelo Augusto
MA
Christoffolete
Nilana M T
NM
Barros
Adriana K
AK
Carmona
D052436:Adipose Tissue, White / Q000201:enzymology / Q000378:metabolism; D000595:Amino Acid Sequence; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D020134:Catalytic Domain; D002403:Cathepsins / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D057056:Cysteine Proteases / Q000378:metabolism / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D020738:Leptin; D011994:Recombinant Proteins; D002403:Cathepsins; D057056:Cysteine Proteases; C028217:cathepsin S