Glycoprotein 130 (gp130) is a signal-transducing receptor widely expressed across tissues and serves as a key mediator for the interleukin-6 (IL-6) family of cytokines, including IL-6, IL-11, Leukemia Inhibitory Factor (LIF), Ciliary Neurotrophic Factor (CNTF), and Oncostatin M (OSM) [1]. Gp130 does not directly bind cytokine ligands. Rather, cytokines initially engage their cognate α-receptors (such as IL-6Rα), which subsequently facilitates the recruitment of gp130 to form a high-affinity receptor complex capable of initiating intracellular signaling [2]. Upon activation, gp130 undergoes conformational changes that enable Janus kinases (JAKs) to phosphorylate intracellular tyrosine residues, creating docking sites for STAT transcription factors (mainly STAT3) [3, 4]. In addition to JAK/STAT signaling, gp130 can activate the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways, giving it broad influence over cell survival, proliferation, metabolism, and differentiation [1, 5, 6]. Gp130 is expressed ubiquitously, but it has particularly important roles in the immune system, heart, liver, nervous system, and skeletal muscle.

In skeletal muscle, gp130 is widely expressed across muscle, stromal, and immune cells, enabling many cell types to respond to IL-6. However, the membrane-bound IL-6 receptor (IL-6Rα) is limited mainly to certain immune cells, such as macrophages and T cells, allowing them to signal via classical IL-6 signaling. Other cells lacking IL-6Rα can still respond through IL-6 trans-signaling, where IL-6 binds soluble IL-6R (sIL-6R) to activate gp130. This enables IL-6 to influence diverse processes in muscle, including inflammation, repair, and adaptation [5, 7, 8]. During exercise or metabolic stress, AMP-activated protein kinase (AMPK) activation enhances glucose uptake by promoting glucose transporter 4 (GLUT4) translocation to the plasma membrane, independent of insulin, and increases lipid oxidation by phosphorylating and inhibiting acetyl-CoA carboxylase (ACC), which lowers malonyl-CoA levels and facilitates fatty acid entry into mitochondria for β-oxidation. IL-6/gp130 signaling can activate STAT3, PI3K/AKT, and AMPK, linking cytokine signaling to metabolic adaptation by improving glucose utilization and enhancing lipid metabolism. These pathways also converge on peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1α), a master regulator of mitochondrial biogenesis, which drives transcription of genes involved in oxidative phosphorylation and energy production [7,8,9,10,11,12]. Beyond metabolism, IL-6/gp130-mediated activation of STAT3 and MAPK/ERK pathways supports muscle repair by stimulating satellite cell proliferation and differentiation, modulating immune cell infiltration, and coordinating extracellular matrix remodeling. Collectively, these signaling mechanisms ensure that skeletal muscle efficiently adapts to energetic demands while maintaining regenerative capacity after injury [13,14,15].

The connection between gp130 signaling and insulin resistance lies primarily in the induction of Suppressor of Cytokine Signaling 3 (SOCS3). Chronic activation of gp130 by cytokines such as IL-6 leads to sustained JAK/STAT3 signaling and consequent upregulation of SOCS3 [16,17,18]. SOCS3 interferes with insulin signaling by binding to the insulin receptor and insulin receptor substarte-1 (IRS-1), blocking their phosphorylation and downstream activation of the PI3K/AKT pathway. This disruption reduces GLUT4 translocation and glucose uptake in skeletal muscle [12, 17, 19]. While gp130 activation during exercise can improve glucose metabolism through AMPK and transient STAT3 activation, sustained stimulation contributes to insulin resistance, particularly in obesity, type 2 diabetes, and chronic inflammation [18, 20, 21]. Most of the current data derives from rodent models and cell culture, with limited direct confirmation in humans.

Gp130 also exists in a soluble form (sgp130), which acts as a selective antagonist of IL-6 trans-signaling. It binds the IL-6/sIL-6R complex, preventing its interaction with membrane-bound gp130 and thereby blocking trans-signaling without affecting classical IL-6 signaling. This helps regulate IL-6 activity and limits excessive inflammation while preserving its regenerative functions [5]. Zuliani et al. [22] suggest that elevated sgp130 levels may be linked to the presence of insulin resistance, whereas Kraakman et al. [23] report that sgp130 does not improve insulin resistance. The precise role of sgp130 and their impact on insulin metabolism remain poorly understood.

Therefore, the present study aimed to analyze the expression of IL-6–related genes (IL6R, IL6ST – gene encoding gp130) and JAK/STAT pathway components in individuals with overweight and obesity, compared with normal-weight individuals, and to examine their association with insulin sensitivity. It also evaluated the role of serum sgp130, a key regulator of IL-6 signaling, in individuals with overweight and obesity.