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  • Adipocytes play diverse roles in energy homeostasis

    2022-05-27

    Adipocytes play diverse roles in energy homeostasis by controlling energy consumption [8] and function as a source of proteins and cytokines, which mediate numerous physiological functions [9]. Excessive accumulation of adipocytes, as well as an increase in either their size or number, causes obesity [8], which is a significant risk factor for several diseases, including hypertension, diabetes, and cancer [10]. Therefore, understanding the molecular mechanism underlying adipogenesis is essential for developing new modalities for treating obesity. Accumulating evidence reveal that extrinsic factors such as dexamethasone (DEX) and insulin or increased cAMP are can induce genes regulating adipogenesis in vitro [11]. Yet, recent reports demonstrated that, in addition to hormonal cocktails, adipogenesis involves massive secretion of extrinsic factors the form of exosomes [12]. Both pre- and post-adipocytes can secrete exosomes containing microRNAs that regulate communication between Z-VEID-FMK [13]. Moreover, supplementation of culture media with human adipose tissue extract [14] and miR-450a-5p within rat adipose tissue exosome-like vesicles [13] led to enhancement of adipogenesis and adipogenic differentiation, respectively. Exosomes originated from multivesicular bodies (MVBs) are packed with microRNAs, mRNAs, and proteins from the parent cells during their formation, and secreted into extracellular milieu by fusion of MVBs with the plasma membrane [15]. Importantly, exosomes play a key role in intercellular communication to modulate numerous crucial pathophysiological processes, including inflammation, tumor invasion, immune responses, and differentiation by transfer of proteins and nucleic acids [16,17]. Recent study showed that down-regulation of NEU1 and accumulation of oversialylated LAMP1 in tumor cells promoted lysosomal exocytosis of hydrolases and exosomes [18]. Therefore, secretion of biomaterials into the extracellular environment by lysosomal exocytosis can be viewed as a mode of intercellular communication in autocrine or paracrine signaling. However, very little is known about the mechanism and physiological roles of intercellular communication by exosomes through lysosomal exocytosis. Considering the endo/lysosomal origin of exosomes and the role of TRPML1 in endo/lysosomal function, in the present study, we examined the role of TRPML1 in exosomal release and adipogenesis.
    Materials and methods
    Results
    Discussion Intracellular membrane trafficking to lysosomes is indispensable for differentiation of adipocytes, including for the increased autophagic flux to the lysosomes that contributes to cytoplasmic reorganization, degradation of mitochondria by the lysosomes, and formation of lipid droplets [19,20]. Lysosomal membrane trafficking in mature adipocytes participates in acidic lipolysis, in which small lipid droplets are engulfed in autophagosomes and are hydrolyzed in lysosomes upon membrane fusion [21]. These trafficking events involve Ca2+-dependent fusion and fission and are mediated by several membrane proteins, including LAMPs, SNAREs, and ion channels [[22], [23], [24], [25]]. A key protein in membrane fusion and fission is the Ca2+ permeable channel TRPML1, which crucially regulates lysosomal pH and mediates the specific release of Ca2+ from lysosomes [1], thus regulating fusion of late endosomes with lysosomes, lysosomal degradation, lysosomal exocytosis, and plasma membrane repair [[26], [27], [28], [29]]. Considering the crucial roles of TRPML1 in lysosomal functions and membrane trafficking, it is surprising that its role in adipogenesis has not been evaluated before. Exosomes and exosomal miRNAs are key factors regulating cell differentiation [[30], [31], [32], [33]]. miR-450a-5p in exosomes isolated from rat adipose tissue enhances adipogenesis by targeting WISP2, a negative regulator of adipogenesis [13]. Based on these findings, we hypothesized that TRPML1 may modulate exosomal release that is needed for adipogenic differentiation by regulating membrane fusion between MVBs/lysosomes and the plasma membrane. In our study, we found that exosomes act in paracrine and autocrine modes to stimulate adipogenesis. The most noteworthy finding of the present study is that TRPML1 regulated exosomal release by mediating lysosomal exocytosis during adipogenesis. TRPML1, as a Ca2+-permeable channel, controls lysosomal trafficking and fusion of lysosomes with late endosomes, MVBs, autophagosomes, and the plasma membrane [34]. Late endosomes are generally considered as MVBs, and trafficking of late endosomes to the plasma membrane allows the release of exosomes [15]. Although fusion of late endosomes with lysosomes leads to degradation of endosomal content [15], growing evidence in drug-resistant cancer cells indicate that exosomes present in lysosomes are protected from degradation and are released by lysosomal exocytosis, which requires Ca2+ release via TRPMLs [35,36].