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  • Several molecular differences between visceral and subcutane


    Several molecular differences between visceral and subcutaneous adipose tissue have been described. One of the most demarcating differences between adipose depots is the signature of developmental genes, including Hox, Shox, and T-box genes [12], [13]. Lineage tracing studies have revealed key developmental signatures in adipocyte development, such as the Myf5 lineage marking brown adipocytes and a subset of white adipocytes across different fat depots [14], [15]. The mesodermal developmental gene TBX15 has also been shown to mark a subset of white adipocytes which have a higher glycolytic rate [16]. Traditionally, surface markers have been used to establish region specificity and to distinguish adipocyte-lineage Barasertib from other adipose-resident cells, although there is disagreement over the exact panel of surface marker expression in the adipocyte lineage [17], [18]. More extensive reviews on this topic are provided elsewhere [2], [19], [20]. Membrane metallo-endopeptidase (MME/Neprilysin/CD10/CALLA) is a membrane-bound protein with a distinct extracellular protease domain. MME was first isolated from rabbit kidney and described as a thermolysin-like enzyme [21]. Since then, MME has been shown to be well-conserved across different species from C. elegans to mammals [22]. MME is a zinc metalloprotease and shares substrates and structural similarity with several related extracellular proteases, including Endothelin Converting Enzyme 1 (ECE1), Phosphate-regulating neutral endopeptidase X-linked (PHEX), and Kell blood group antigen (KEL) [23], [24], [25]. MME is also expressed in the brain, where the MME knockout mouse has been shown to have an increase in amyloidβ peptides, suggesting that MME may play a role in protection from Alzheimer\'s disease [26]. The whole-body MME knockout (MMEKO) mouse was created in 1995 and was described as a septic shock model because it showed hypersensitivity to treatment with different cytokines [27]. In the context of metabolism, the MMEKO mouse develops age-related obesity. This is thought to be mediated through hyperphagia [28], although the exact mechanism is unclear. Interestingly, whole-body knockdown or overexpression of the Drosophila MME homolog NEP4 decreases larval food intake and decreases the levels of circulating insulin-like peptide DILP1 [29]. In humans, MME is also found in plasma, and circulating levels of MME positively correlate with BMI and HOMA-IR [30]. Additionally, MME mutants have been associated with Charcot-Marie-Tooth disease [31], emphasizing that MME is expressed in a variety of tissue types, including adipose, brain, and lymphatic tissue [26], [27], [28]. MME has been shown to target a variety of small peptides including amyloidβ, insulin B-chain, and several neuropeptides [25], [32]. Additionally, the MME intracellular domain is known interact with PTEN, suggesting it potentially could modify signaling pathways active via the PI3K/Akt pathway [33], [34], [35]. Both adipocytes and preadipocytes express MME, and preadipocytes have been shown to secrete exosome-bound MME, which can be endocytosed by non-adipose cell types such as neuronal cells in vitro [36].
    Materials and methods
    Discussion MME has been shown to have at least three distinct transcripts in humans producing the same 750-bp protein product [64]. The most recent human genome build (GrCh38) has up to 18 different transcripts (coding, non-coding, and predicted) from the MME locus. In rats, these mRNA species have been shown to have tissue-specific expression driven by different promoters resulting in unique 5\' untranslated regions [52]. Truncated transcripts of MME have been reported in previous studies [55], [56]. A truncated form of MME missing exon 16 was identified in human lung tissue and reported to have significantly impaired enzymatic activity [56]. There are also differences in glycosylation of MME in different tissues resulting in tissue-specific differences in molecular weight of MME ranging from 85 to 110 kDa [65]. Our data show differential exon-usage in MME between human subcutaneous and omental preadipocytes in the extracellular N-terminal peptidase domain (exons 12 and 14), suggesting distinct tissue-specific regulation of MME isoforms.