ADAMTS18 Deficiency Leads To Visceral Adiposity And Associated Metabolic Syndrome In Mice

Visceral adiposity is of greater risk than obesity in subcutaneous adipose tissue for diabetes and cardiovascular disease.Its pathogenesis remains unclear,but it is associated with extracellular matrix(ECM)remodeling.A disintegrin and metalloproteinase with thrombospondin motifs(ADAMTSs)are a family of secreted Zn-dependent metalloproteinases that play crucial roles in development and various diseases owing to their ECM remodeling activity.ADAMTS18 is an “orphan ADAMTS” whose function and substrate remain unclear.Here,we showed that Adamts18 m RNA was abundantly expressed in visceral(gonadal)white adipose tissue(v WAT)during the early stage of development after birth.Adamts18 knockout(KO)mice showed increased body fat percentage and larger adipocyte size in v WAT relative to WT littermates,which could be partly attributed to ECM remodeling,especially increased expression of laminin1(LN1)and adipokine thrombospondin1(THBS1)in v WAT.Attenuated ERK1/2 activity,along with increased expression of adipocyte-specific transcription factors PPARγ,C/EBPβ,and marker gene a P2 were detected in v WAT of Adamts18 KO mice.Furthermore,Adamts18 KO mice showed early metabolic syndrome including hyperlipidemia,blood glucose metabolic disorder,and hypertension.ADAMTS18 deficiency promotes atherosclerosis in apolipoprotein E-deficient(Apoe-/-)mice.These results indicate a novel function of ADAMTS18 in v WAT development and associated metabolic disorders.