ZAG alleviates HFD-induced insulin resistance accompanied with decreased lipid depot in skeletal muscle in mice

Abstract

diabetes, hypertension, etc. The causes of insulin resistance are complicated and may vary for different individuals. Nevertheless, the factor most commonly associated with insulin resistance is excess adiposity due to the increase in circulating fatty acids and ectopic lipids (1). Intramuscular lipids are an indispensable energy source for skeletal muscle. These lipids play pivotal roles in metabolism not only for skeletal muscle but also for the entire body. The accumulation of ectopic lipids in skeletal muscle is thought to be involved in the etiology of type II diabetes and insulin resistance by suppressing insulin-stimulated glucose uptake (2, 3). Skeletal muscle accounts for 80% of insulin-stimulated glucose uptake (4). It is the primary site of insulin-stimulated glucose uptake and metabolism (4, 5). Earlier studies, both in humans (6) and in animal models (7), indicated that intramuscular lipid accumulation was associated with insulin resistance, thereby providing a potential link between dysregulated fatty acid metabolism in skeletal muscle and insulin resistance (6-9). Zinc-2-glycoprotein (ZAG) is a 43 kDa soluble glycoprotein, first isolated from human plasma. However, a previous study showed that ZAG was produced in many tissues, Abstract Over the past two decades, intramuscular lipids have been viewed as a cause of insulin resistance due to their ability to suppress insulin-stimulated glucose uptake in skeletal muscle. Zinc-2-glycoprotein (ZAG) is an adipokine involved in lipolysis of white adipose tissue (WAT). To investigate the action of ZAG on insulin resistance induced by a high-fat diet (HFD), which affects the intramuscular fat, mice were divided into three groups, normal diet, HFD, and ZAG treatment under HFD (HFZ). The results showed that the insulin sensitivity of ZAG-treated mice was significantly improved. The body weight, WAT weight, and intramuscular fat were significantly decreased in the HFZ group compared with the HFD group. The lipolytic enzymes, including phosphorylation of hormonesensitive lipase and adipose triglyceride lipase, were significantly upregulated in the skeletal muscle of mice that received the ZAG treatment compared with the HFD group. Insulin signaling proteins, such as phosphorylation of insulin receptor substrate 1 and cell membrane glucose transporter type 4, were also significantly increased in the skeletal muscle of the ZAG-treated group. Furthermore, a metabolic rate study showed that ZAG overexpression increases the respiratory exchange ratio and heat production. In vitro, ZAG treatment promotes glucose uptake and decreases intracellular lipids in C2C12 myotubes. Taken together, these data showed that overexpression of ZAG alleviates HFD-induced insulin resistance in mice, along with decreasing the lipid content of skeletal muscle.-Gao, S-X., J. Guo, G-Q. Fan, Y. Qiao, R-Q. Zhao, and X-J. Yang. ZAG alleviates HFD-induced insulin resistance accompanied with decreased lipid depot in skeletal muscle in mice.

Association between circulating zinc-α2-glycoprotein levels and the different phenotypes of polycystic ovary syndrome

“…Kabil SL et al recently showed reduced hepatic ZAG expression in diabetic rats maintained on a high-fat diet (HFD) [21]. Additionally, one study showed that the overexpression of ZAG alleviated HFD-induced IR and decreased the lipid contents of muscles in mice [22]. Another study showed that ZAG overexpression could protect against nonalcoholic fatty liver disease (NAFLD) in vivo or in vitro by ameliorating hepatic steatosis, IR, and inflammation [23].…”

The association of the adipokine zinc‐alpha2‐glycoprotein with non‐alcoholic fatty liver disease and related risk factors: A comprehensive systematic review

“…Numerous studies have confirmed beneficial effects of ZAG on glycaemic control. 29,34,38,[42][43][44]46,[49][50][51]54,56,59 ZAG promotes insulin sensitivity and glucose tolerance through the activation of insulin receptor substrate (IRS)/AKT signalling pathway. 34 Analysis of human adipose tissue samples showed a positive association between adipose tissue insulin sensitivity and the expression of GLUT4 mRNA and ZAG protein content in subcutaneous adipose tissue (P < .05).…”

“…52 In addition, a significant upregulation of lipolytic enzymes including phosphorylation of HSL and ATGL in the skeletal muscle of mice was observed after administration of ZAG (25 µg for 30 minutes). 54 Due to an increased use of lipids by muscle and brown adipose tissue after ZAG administration (50 µg/day intravenously, for 10 days) to mice, levels of triglyceride and non-esterified fatty acids decreased by 25% and 62%, respectively. 56 Moreover, injection of ZAG recombinant plasmid to mice fed a HFD led to a great reduction in hepatic triglyceride by increasing phosphorylated protein kinase A (PPKA) expression, promoting phosphorylation of HSL, and decreasing protein levels of stearoyl-CoAdesaturase1 (SCD1), acyl-CoA synthetase-1 (ACSS1), hepatic fatty acid translocase (CD36)…”

“…found that loss of adipose tissue might result from the lipolytic effect of ZAG accompanied by an increase in energy expenditure, since a dose-dependent increase in the expression of UCP-1 in brown adipose tissue was observed. A recent study performed by Gao et al54 indicated that intramuscular fat was markedly reduced in the skeletal muscle of ZAG-treated mice (25 µg) compared with the HFD group.The association between ZAG and obesity-related parameters has also been documented in humans. In this regard, Balaz et al44 demonstrated that ZAG protein and mRNA levels were significantly reduced in subcutaneous adipose tissue of morbidly obese individuals with BMI > 45 kg/m 2 (P < .001).…”

Zinc-α2-glycoprotein promotes skeletal muscle lipid metabolism in cold-stressed mice

“…As a new adipocytokine, more and more attention is being paid to ZAG, aiming at the prevention of obesity and energy metabolism disorders [12,13]. In a previous study, we found that ZAG decreases skeletal muscle lipid content and, therefore, alleviates insulin resistance in high-fat mice [14]. However, whether ZAG exerts its function in the skeletal muscle energy metabolism during cold stress, and whether it is involved in the acclimation to low temperatures is still unknown.…”