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  • In the context of metabolism the MMEKO mouse develops age

    2020-08-04

    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 GW-1100 in vitro [36].
    Materials and methods
    Results
    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. In terms of its protease activity, MME has a broad range of substrates being able to target glucagon, bradykinin, GLP1, and several other classes of circulating small molecules [25]. MME has been shown to target free insulin B-chain [32], although whether MME could target and degrade the insulin receptor is unknown. Our data suggest that MME is affecting some aspect of INSR trafficking such that the alpha subunit accumulates, whereas the beta subunit does not. Several factors can contribute to this observation. One is that the alpha subunit has a longer half-life than the beta subunit in the presence of insulin [66]. Another is that the glycosylation state of the receptor affects not only western blot detection but also the processing and degradation of the receptor [67]. Lastly, previous research has shown that glucose deprivation causes aberrant glycosylation of the insulin proreceptor that results in an accumulation of the beta subunit but not the alpha subunit [68].