High-fat diet and palmitate inhibits FNDC5 expression via AMPK-Zfp57 pathway in mouse muscle cells

Modern lifestyles, including high-calorie diets and prevalent sedentary behavior, significantly contribute to the high incidence of obesity and metabolic diseases, such as dyslipidemia, diabetes mellitus and nonalcoholic fatty liver disease [1]. High-fat diet promotes ectopic accumulation of lipid in non-adipose tissues, particularly skeletal muscle, resulting in lipotoxicity, inflammation, and insulin resistance [2,3]. Excessive saturated free fatty acids (FFA) in plasma, such as palmitate, presents a key pathogenic risk factor for diabetes and obesity [4]. Muscle, liver and adipose tissue, as peripheral tissue, metabolize free fatty acids in blood as a major source of energy [5]. And skeletal muscle is the primary site responsible for postprandial insulin-mediated glucose uptake. Skeletal muscle insulin resistance plays an important role in the pathogenesis of type 2 diabetes [6]. Skeletal muscle is additionally an endocrine organ that secretes diversity of myokines, such as myonectin, fibroblast growth factor-21, musclin, irisin, IL-6 and IL-13, which regulate the metabolic functions of other tissues and organs [7].

Irisin was initially identified by Boström and his group as a novel exercise-regulated myokine implicated in reducing blood glucose and improving insulin resistance. It is produced by proteolytic cleavage of FNDC5 and contains 112 amino acids [8]. FNDC5 is a glycosylated type Ⅰ membrane protein which comprises a N-terminal signal peptide, a Fibronectin Ⅲ domain, a transmembrane domain and a cytoplasmic tail [9]. Earlier reports showed that endurance exercise activates PPAR-γ co-activator-1 α (PGC-1α) and characterized irisin as a PGC-1α-dependent myokine secreted from skeletal muscle during exercise [8]. High-fat diet and obesity have additionally been associated with increase of FNDC5 expression in mouse muscle tissue in a number of studies [10,11]. However, some researchers have reported decrease of FNDC5 in type 2 diabetic patients and db/db mice [12,13]. These conflicting results may be attributable to differences in the severity or duration of insulin resistance.

Zfp57 belongs to the zinc-finger protein (ZFP) family, a large group of transcription factors in mammals. ZFPs is consisted of more than 30 zinc fingers that involve in binding specific DNA and RNA [14]. Zfp57 was originally cloned from a mouse teratocarcinoma cell line [15] and shown to recruit Krüppel-associated box (KRAB)-associated protein 1 (KAP1) to multiple imprinting control regions and participate in the regulation of genome imprinting through maintenance of DNA methylation [16]. Previous studies have demonstrated that Zfp57 mutation triggers transient neonatal diabetes with ketoacidosis [17]. However, the regulatory association between Zfp57 and FNDC5 remains unclear at present.

5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK), could sense intracellular energy. And AMPK has a crucial regulatory role in cellular metabolism [18], which is indicated in skeletal muscle glucose transport during exercise [19]. The AMP analog, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), could activate AMPK and be positively associated with increase of glucose uptake in skeletal muscle [20]. Palmitate is reported to inhibit AMPK activity in endothelial cells via protein phosphatase 2A (PP2A) activation [21]. When insulin binds to insulin receptor, the downstream substrates phosphatidylinositol-3 kinase (PI3K) and the protein kinase B (Akt) will be activated, leading to GLUT4 glucose transporter translocation and increased glucose uptake. Disturbance of the PI3K-Akt signaling pathway is involved in insulin resistance and type 2 diabetes [8]. However, little is known about the potential regulatory effects of AMPK signaling on Zfp57 and FNDC5 expression and activity in muscle cells.

In this study, we investigated the expression patterns of FNDC5 and Zfp57 in muscle cells in response to HFD or palmitate. Our results validated the hypothesis that Zfp57 participates in regulation of FNDC5 expression. The involvement of AMPK signaling in regulation of Zfp57 and FNDC5 expression with the treatment of palmitate and the roles of these proteins in insulin resistance were further explored.

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