**1. Introduction**

Gestational diabetes mellitus (GDM) is a type of unbalanced glucose tolerance that occurs during pregnancy, which affects approximately 10% of pregnancies worldwide [1]. The clinical and public health relevance of gestational diabetes mellitus has been widely debated due to its increasing incidence and resulting negative economic impact, and the potential for severe GDM-related pregnancy complications [2]. In addition, the American Diabetes Association (ADA) "Management of Diabetes in Pregnancy: Standards of Medical Care in Diabetes 2019" recommends diabetes care from preconception to postpartum [3]. Several risk factors, including obesity, history of previous GDM diagnosis, advanced maternal age, and gestational hypertension, have been implicated in the pathogenesis of GDM [4,5]. In general, specific risks of uncontrolled diabetes in pregnancy include spontaneous abortion, fetal anomalies, preeclampsia, fetal demise, macrosomia, neonatal hypoglycemia, and neonatal hyperbilirubinemia, among others. In addition, diabetes in pregnancy may increase the risk of obesity and type 2 diabetes in the offspring later in life [6,7]. Thus, it is important to understand the pathogenesis of GDM.

Fetuin-A belongs to the cystatin protease inhibitor superfamily [8]. It is the major human secretory protein derived from the liver and adipose tissue and performs several pathophysiological functions

related to insulin sensitivity [9], glucose tolerance [10], and even soft tissue calcification [11]. In the liver and skeletal muscles, fetuin-A, per se, is an endogenous inhibitor of the insulin receptor [12] and is crucial for lipid-induced insulin resistance [13]. By binding to the β-subunit of the insulin receptor, fetuin-A inhibits the activity of the insulin receptor, followed by the blocking of insulin-stimulated GLUT4 translocation and Akt activation [14]. In addition, fetuin-A is also involved in inflammatory signaling [13]. Fetuin-A acts as an endogenous ligand for the innate immune Toll-like receptor (TLR)-4, thus promoting lipid-induced insulin resistance. Moreover, fetuin-A is associated with several metabolic disorders. High serum fetuin-A concentrations are observed in patients with several metabolic syndromes, including insulin resistance, fatty liver, and diabetes [10,15]. A recent study also showed that the circulating fetuin-A concentration increases in GDM women [16], however, the underlying molecular mechanism is still unclear.

The centrosome is the major microtubule organization center that orchestrates microtubule networks for proper cell migration and division [17]. It comprises mother and daughter centrioles and the surrounding pericentriolar materials (PCM). The duplication of the centrosome coordinates with DNA replication. During the S phase, each centriole functions as a platform for a new procentriole to grow. The duplicated centrosomes start to separate to the opposite site of the nucleus, followed by the establishment of mitotic spindle poles for proper chromosome segregation in the M phase. Thus, precise control of centrosome homeostasis is important to maintain cell growth and genomic instability [18,19].

The centrosome also contributes to the growth of the primary cilium [20]. The primary cilium is the cellular protrusion that receives chemical or mechanical signals for proper development and differentiation [21]. The primary cilium is composed of the central microtubule-built axoneme and the overlying ciliary membrane [22]. On the axoneme, intraflagellar transporters regulate cilia dynamics and functions via anterograde and retrograde transportations. Recent studies have also demonstrated that the primary cilia play important roles in placentation during early pregnancy [23].

In this study, we enrolled placental samples from twenty pregnant women with GDM and twenty non-GDM pregnant women and found that the abundance of fetuin-A was upregulated in terms of mRNA and protein levels. The upregulated fetuin-A impeded cell cycle progression and induced apoptosis. In addition, centrosome amplification with disorganized microtubule arrays was observed in fetuin-A-treated placental cells. Furthermore, fetuin-A inhibited autophagy, therefore, blocking the growth of the primary cilium. Thus, our study uncovered the effect of fetuin-A on the regulation of placental cell growth and ciliogenesis.
