Novel properties of myoferlin in glucose metabolism via pathways involving modulation of adipose functions

Abstract

While adipose tissue is required to maintain glucose metabolism, excessive calorie intake induces obesity via mechanisms including accelerated proliferation and differentiation of preadipocytes, leading to insulin resistance. Here, we investigated the role of myoferlin (MYOF), a ferlin family protein, in regulating glucose metabolism by mainly focusing on its unknown role in adipose tissue. Whereas young MYOF knockout (KO) mice on a normal diet showed aggravated glucose tolerance and insulin sensitivity, those on a high-fat diet (HFD) showed preserved glucose tolerance with an attenuated gain of body weight, reduced visceral fat deposits, and less severe fatty liver. The Adipose MYOF expression was reduced by aging but was restored by an HFD along with the retained expression of NFAT transcription factors. Lossof-function of MYOF in preadipocytes suppressed proliferation and differentiation into mature adipocytes along with the decreased expression of genes involved in adipogenesis. The MYOF expression in preadipocytes was reduced with differentiation. Attenuated obesity in MYOF KO mice on an HFD was also accompanied with increased oxygen consumption by an unidentified mechanism and with reduced adipose inflammation due to less inflammatory macrophages. These insights suggest that the multifunctional roles of MYOF involve the regulation of preadipocyte function and affect glucose metabolism bidirectionally depending on consumed calories. K E Y W O R D Sadipocyte differentiation, insulin resistance, myoferlin, obesity | 2793 NOZATO eT Al.

A Mixture of Endocrine Disrupting Chemicals Associated with Lower Birth Weight in Children Induces Adipogenesis and DNA Methylation Changes in Human Mesenchymal Stem Cells

“…Most DMPs (n = 158) were shared between the hMSCs exposed to the 1X and the 1000X Mix G1 (Table S4). These included hypermethylated DMP annotated to the FGF9, MYOF, ZNRF3, ACSM3, AMN, APBB2, EGFL6, RBMS1, GNAQ, PTPRJ, and TOMM7 genes known to be important for osteogenesis and thermogenesis [50,51], adipogenesis [52], body fat distribution [53], fatty acid metabolism [54,55], obesity [56][57][58], glucose metabolism [59], type 2 diabetes and insulin signaling [60,61], respectively. Several DMPs were also hypomethylated in the FFAR2, IRS-1, MAF, and PGM1 genes known to be important for lipid accumulation [62], adipocyte differentiation [63,64], and glycogen metabolism and adipogenesis [65,66], respectively.…”

Snow crab (Chionoecetes opilio) hemocytes and hepatopancreas transcriptomes: identification, validation, and application of immune-relevant biomarkers of exposure to noise

“…While Myoferlin has primarily been studied in mammalian muscle, where it plays roles in myoblast fusion and endocytosis by endothelial cells (Doherty et al, 2005), it is now known to also have important functions in many mammalian cell types including phagocytes (e.g. macrophages and neutrophils), adipocytes and cancer cells (Miyatake et al, 2018;Nozato et al, 2020;Gupta et al, 2021). Functional annotations associated with myof include "plasma membrane repair" and "extracellular exosome" (Supplemental Table 2); extracellular exosomes (also called extracellular microvesicles) are important components of several biological processes including tissue homeostasis, organ remodeling, and cell-cell communication (Ratajczak and Ratajczak, 2020 and references therein).…”

“…For example, Myoferlin plays a key role in mouse phagocyte function by regulating lysosomal exocytosis (Miyatake et al, 2018). In addition, myof knockout mice on a high-fat diet had attenuated obesity, altered glucose metabolism, and lower adipose inflammation associated with fewer inflammatory macrophages compared with those on a normal diet (Nozato et al, 2020). In human pancreatic cancer cells, Myoferlin is a membrane repair factor that protects against membrane damage and regulates lysosome function, with lower Myoferlin expression alleviating malignant phenotypes (Wang et al, 2013;Zhu et al, 2019;Gupta et al, 2021).…”