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.

Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK2

“…2D and 2E). Transductions with other shRNA sequences did not grow and consequently died, as in agreement with literature (12).…”

“…3) with mock shRNA. Consistent with literature (12,50), it needs to be mentioned that a higher knock down led to growth arrest and cell death. As a filtering criterion, we only considered proteins that were reproducibly (P1, p Ͻ .05) more than 1.25-fold (significance B, Intensity versus log2FC, p Ͻ .05) (44) increased or decreased as being influenced by TPP2 if they were changed in the same direction in at least two out of the three screens.…”

“…That TPP2 is an essential protein is supported by the finding that homozygous knock down in mice and Caenorhabditis elegans is lethal (12). TPP2 is involved in antigen processing (13)(14)(15)(16)(17)(18), cell growth, DNA damage repair and carcinogenesis (19 -22), fat metabolism, feeding behavior, and obesity (12,23). While the majority of those processes has been linked to TPP2 by describing individual phenotype and expressional changes of TPP2 as well as connected individual proteins (24 -26), only antigen processing and feeding behavior have been directly related to TPP2 peptidase activity by identifying involved peptide substrates (6,9,10,23).…”

“…That TPP2 is an essential protein is supported by the finding that homozygous knock down in mice and Caenorhabditis elegans is lethal (12). TPP2 is involved in antigen processing (13)(14)(15)(16)(17)(18), cell growth, DNA damage repair and carcinogenesis (19 -22), fat metabolism, feeding behavior, and obesity (12,23).…”

“…TPP2 has been shown to generate a few specific epitopes via its endopeptidase activity, for instance, for specific HLA allele mediated peptide presentation (10,11,17,27). It has been suggested a role of TPP2 in obesity relies on exopeptidase cleavage of the satiety signaling neuropeptide cholecystokinin-8, which subsequently regulates feeding behavior (12,17,28). The uniform expression of TPP2 in the brain (29,30), including regions that are not involved in the regulation of feeding behavior, suggests a hitherto general function in neuronal cells.…”