title: Positive feedback regulation between adiponectin and T-cadherin impacts adiponectin levels in tissue and plasma of male mice.
abstract: Adiponectin (Adipo), a multimeric adipocyte-secreted protein abundant in the circulation, is implicated in cardiovascular protective functions. Recent work documented that Adipo locally associates with responsive tissues through interactions with T-cadherin (Tcad), an atypical, glycosylphosphatidylinositol (GPI)-anchored cadherin cell surface glycoprotein. Mice deficient for Tcad lack tissue-associated Adipo, accumulate Adipo in the circulation, and mimic the Adipo knockout (KO) cardiovascular phenotype. In reverse, Tcad protein is visibly reduced from cardiac tissue in Adipo-KO mice, suggesting interdependent regulation of the 2 proteins. Here, we evaluate the effect of Adipo on Tcad protein expression. Adipo and Tcad proteins were colocalized in aorta, heart, and skeletal muscle. Adipo positively regulated levels of Tcad protein in vivo and in endothelial cell (EC) cultures. In Tcad-KO mice, binding of endogenous and exogenously administered Adipo to cardiovascular tissues was dramatically reduced. Consistently, knockdown of Tcad in cultured murine vascular ECs significantly diminished Adipo binding. In search for a possible mechanism, we found that enzymatic cleavage of Tcad with phosphatidylinositol-specific phospholipase C increases plasma Adipo while decreasing tissue-bound levels. Similarly, pretreatment of cultured ECs with serum containing Adipo attenuated phosphatidylinositol-specific phospholipase C-mediated Tcad cleavage. In vivo administration of adenovirus producing Adipo suppressed plasma levels of GPI phospholipase D, the endogenous cleavage enzyme for GPI-anchored proteins. In conclusion, our data show that both circulating and tissue-bound Adipo levels are dependent on Tcad and, in reverse, regulate tissue Tcad levels through a positive feedback loop that operates by suppressing phospholipase-mediated Tcad release from the cell surface.
authors.affiliation: Departments of Metabolic Medicine (K.M., Y.F., N.M., T.M., A.H., R.S., Y.T., S.M., M.Y., K.I., H.N., S.K., T.F., I.S.) and Metabolism and Atherosclerosis (A.H., S.K., T.F.), Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; and 3Sanford-Burnham Medical Research Institute (B.R.), National Institutes of Health-Designated Cancer Center, Development, Aging, and Regeneration Program, La Jolla, California 92037.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Matsuda
authors.forename: Yuya
authors.initials: Y
authors.lastname: Fujishima
authors.forename: Norikazu
authors.initials: N
authors.lastname: Maeda
authors.forename: Takuya
authors.initials: T
authors.lastname: Mori
authors.forename: Ayumu
authors.initials: A
authors.lastname: Hirata
authors.forename: Ryohei
authors.initials: R
authors.lastname: Sekimoto
authors.forename: Yu
authors.initials: Y
authors.lastname: Tsushima
authors.forename: Shigeki
authors.initials: S
authors.lastname: Masuda
authors.forename: Masaya
authors.initials: M
authors.lastname: Yamaoka
authors.forename: Kana
authors.initials: K
authors.lastname: Inoue
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nishizawa
authors.forename: Shunbun
authors.initials: S
authors.lastname: Kita
authors.forename: Barbara
authors.initials: B
authors.lastname: Ranscht
authors.forename: Tohru
authors.initials: T
authors.lastname: Funahashi
authors.forename: Iichiro
authors.initials: I
authors.lastname: Shimomura
mesh_terms: D052242:Adiponectin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects; D000939:Epitopes; D025461:Feedback, Physiological; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism / Q000494:pharmacology
chemical_list: D052242:Adiponectin; D015820:Cadherins; D000939:Epitopes; C099972:H-cadherin; D054801:Phosphoinositide Phospholipase C