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  • In regards to regional variation


    In regards to regional variation in metabolic behavior of adipose tissue, subcutaneous adipose tissue transplantation has been shown to reprogram visceral adipose tissue to have subcutaneous-like phenotypic behavior, whereas visceral-to-subcutaneous transplantation does not promote a more detrimental phenotype [7], [74]. MME, as a membrane-bound protease, can modify the local milieu in a substrate-specific manner in an adipose transplantation, whereas the absence of MME would not worsen the depot. Thus, MME may also be involved in adipose tissue reprogramming by degrading the appropriate hormones to promote a metabolically-beneficial phenotype. Although we have focused on MME as one of the central differences between subcutaneous and visceral preadipocytes, the gene RGDfK synthesis in both human and mouse datasets showed several other distinct differences. For example, another differentially RGDfK synthesis expressed gene, 4-aminobutyrate aminotransferase (ABAT), has been shown to be differentially expressed between brown and white adipocytes [75] and may be involved in the maintenance of mitochondria [76], which are much higher in brown than in white adipocytes. Thus, ABAT may also be involved in the metabolic differences within different types of white adipocytes, such as between subcutaneous and visceral adipocytes. Similarly, the remaining differentially expressed genes, Integrin beta 8 (ITGB8) and Junction Adhesion Molecule A (F11R), may play an as-of-yet unidentified role in the phenotypic differences between depot-specific adipocytes.
    Author contributions
    Acknowledgements We would like to thank James Kirkland for providing the human preadipocyte stromal vascular isolates; Bao Lu and Craig Gerard for providing breeding pairs of the MMEKO mice. A.K.R. was supported by NIH grant T32 DK007260-37. This work was supported by P30DK036836, R01DK0835659 and R37031036.
    Introduction Tripeptidyl-peptidase II (TPP II) is a cytosolic subtilisin-like serine peptidase with a very large (>4MDa) homooligomeric quarternary structure [1]. It is present in most eukaryotes and as the name implies, the main activity is removal of tripeptides from the N-terminus of longer peptides. In addition to the exopeptidase activity, TPP II also exhibits an endopeptidase activity [2]. This is essential for the generation of at least one MHC class I epitope [3], although the overall role for TPP II in the generation of epitopes for MHC class I antigen presentation is disputed [4], [5], [6], [7], [8], [9]. TPP II is held to be of importance in intracellular protein degradation, as it can produce easily digestible substrates for aminopeptidases from the peptides released by the proteasome (the majority of which is 5–8 amino acid residues [10]) and could thereby facilitate the release of free amino acids. Indeed, TPP II has been reported to be upregulated during conditions of accelerated protein degradation, such as in muscle tissue during sepsis [11] and serum starvation in cell cultures [12]. Cells with elevated levels of TPP II seem to be more resilient towards inhibition of the proteasome [13], and to form more rapidly growing tumours in vitro[12]. This is ominous with regard to the proteasome as a cancer drug target, since resistance to drugs might occur due to increased levels of TPP II [14]. Cytosolic protein degradation is usually carefully regulated, since uncontrolled proteolysis would be deleterious to the cell and a waste of energy. There has been no feedback regulation mechanism reported for TPP II to date. Instead, activity is proposed to be controlled by complex formation, since dimers have only 10% of the activity of the full-size complex [15]. In the complex, a substrate has to penetrate an intricate cavity system with two openings of 20×22Å and 15×35Å to reach the active site, which would sterically hinder proteins from being degraded [16]. In accordance with this, TPP II has never been reported to degrade intact proteins and the largest substrate to be cleaved by TPP II is a 41 amino acid long peptide [2].