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Tripeptidyl peptidase II promotes fat formation in a conserved fashion.

ABSTRACT: Tripeptidyl peptidase II (TPPII) is a multifunctional and evolutionarily conserved protease. In the mammalian hypothalamus, TPPII has a proposed anti-satiety role affected by degradation of the satiety hormone cholecystokinin 8. Here, we show that TPPII also regulates the metabolic homoeostasis of Caenorhabditis elegans; TPPII RNA interference (RNAi) decreases worm fat stores. However, this occurs independently of feeding behaviour and seems to be a function within fat-storing tissues. In mammalian cell culture, TPPII stimulates adipogenesis and TPPII RNAi blocks adipogenesis. The pro-adipogenic action of TPPII seems to be independent of protease function, as catalytically inactive TPPII also increases adipogenesis. Mice that were homozygous for an insertion in the Tpp2 locus were embryonic lethal. However, Tpp2 heterozygous mutants were lean compared with wild-type littermates, although food intake was normal. These findings indicate that TPPII has central and peripheral roles in regulating metabolism and that TPPII actions in fat-storing tissues might be an ancient function carried out in a protease-independent manner.

SUBMITTER: McKay RM

PROVIDER: S-EPMC2267238 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Tripeptidyl peptidase II promotes fat formation in a conserved fashion.

McKay Renée M RM McKay James P JP Suh Jae Myoung JM Avery Leon L Graff Jonathan M JM

EMBO reports 20071012 12

Tripeptidyl peptidase II (TPPII) is a multifunctional and evolutionarily conserved protease. In the mammalian hypothalamus, TPPII has a proposed anti-satiety role affected by degradation of the satiety hormone cholecystokinin 8. Here, we show that TPPII also regulates the metabolic homoeostasis of Caenorhabditis elegans; TPPII RNA interference (RNAi) decreases worm fat stores. However, this occurs independently of feeding behaviour and seems to be a function within fat-storing tissues. In mammal ...[more]

PMID: 17932511

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Project description:The endometrium undergoes cyclic remodelling throughout the menstrual cycle in preparation for embryo implantation which occurs in a short window during the mid-secretory phase. It is during this short 'receptive window' that the endometrial luminal epithelium acquires adhesive capacity permitting blastocysts firm adhesion to the endometrium to establish pregnancy. Dysregulation in any of these steps can compromise embryo implantation resulting in implantation failure and infertility. Many factors contribute to these processes including TGF-β, LIF, IL-11 and proteases. Tripeptidyl peptidase 1 (TPP1) is a is a lysosomal serine-type protease however the contribution of the TPP1 to receptivity is unknown. We aimed to investigate the role of TPP1 in receptivity in humans.In the current study, TPP1 was expressed in both epithelial and stromal compartments of the endometrium across the menstrual cycle. Expression was confined to the cytoplasm of luminal and glandular epithelial cells and stromal cells. Staining of mid-secretory endometrial tissues of women with normal fertility and primary unexplained infertility showed reduced immunostaining intensity of TPP1 in luminal epithelial cells of infertile tissues compared to fertile tissues. By contrast, TPP1 levels in glandular epithelial and stromal cells were comparable in both groups in the mid-secretory phase. Inhibition of TPP1 using siRNA compromised HTR8/SVneo (trophoblast cell line) spheroid adhesion on siRNA-transfected Ishikawa cells (endometrial epithelial cell line) in vitro. This impairment was associated with decreased sirtuin 1 (SIRT1), BCL2 and p53 mRNA and unaltered, CD44, CDH1, CDH2, ITGB3, VEGF A, OSTEOPONTIN, MDM2, CASP4, MCL1, MMP2, ARF6, SGK1, HOXA-10, LIF, and LIF receptor gene expression between treatment groups. siRNA knockdown of TPP1 in primary human endometrial stromal cells did not affect decidualization nor the expression of decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1). Taken together, our data strongly suggests a role for TPP1 in endometrial receptivity via its effects on epithelial cell adhesion and suggests reduced levels associated with unexplained infertility may contribute to implantation failure.

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Tripeptidyl peptidase II promotes fat formation in a conserved fashion.

Publications

Tripeptidyl peptidase II promotes fat formation in a conserved fashion.

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