Metabolic dysfunction-associated steatotic liver disease (MASLD) is the latest term for a steatotic liver disease associated with Metabolic Syndrome (MS) (Chan et al., 2023). This term was introduced in a multi-society Delphi consensus statement on the new nomenclature for fatty liver disease, replacing the term non-alcoholic fatty liver disease (NAFLD). The consensus provided a revised definition that included the presence of steatotic liver disease along with at least one of five cardiometabolic risk factors. These include increased body mass index (BMI) or waist circumference (WC), impaired glucose metabolism, high blood pressure, elevated triglyceride (TG) levels, or low high-density lipoprotein cholesterol (HDL-C) levels (Rinella et al., 2023). Currently, MASLD is the most common cause of chronic liver disease and a leading contributor to liver-related morbidity and mortality (Zhou et al., 2023).

The rising global prevalence of obesity, type 2 diabetes mellitus (T2DM), and MS has contributed to a marked increase in the MASLD, now recognized as a major public health concern. At present, MASLD affects more than one-third of the global adult population (Miao et al., 2024). The pathogenesis of MASLD involves multiple mechanisms, including environmental, metabolic and genetic factors (Li et al., 2024).

The liver plays a central role in the regulation of whole-body carbohydrate and lipid homeostasis. Insulin resistance (IR) is a key pathogenic feature of MS and is now recognized as the most common risk factor for the development and progression of MASLD (Bansal and Bansal, 2024; Sakurai et al., 2021; Bo et al., 2024). Appropriate hepatic insulin signaling is crucial for maintaining the metabolism of these nutrients (Liu et al., 2017). Previous studies have indicated that hepatic GLUT-2 expression increases in diet-induced IR (Sharawy et al., 2016; Mathur et al., 2015). GLUT-2 transports glucose across the liver membrane in a bidirectional manner, allowing glucose flux necessary for both glycolysis and gluconeogenesis (Thorens, 2015). There is sufficient evidence that in states of reduced hepatic insulin sensitivity, the suppressive effect of insulin on gluconeogenesis is impaired, and this is associated with alterations in the insulin signaling pathway (Chao et al., 2019; Santos-Laso et al., 2022). These alterations lead to an increased expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (Glucose-6-Pase) (Honma et al., 2018). Another important regulator of gluconeogenesis is AMP-activated protein kinase (AMPK), which plays a fundamental role in inhibiting this process and maintaining normoglycemia (Herzig and Shaw, 2018). Additionally, there are changes in the action of factors that control the expression of these enzymes, such as the forkhead box O1 (FOXO-1) transcription factor and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) (Teaney and Cyr, 2023).

Moreover, IR is associated with the downregulation of insulin receptor substrate 1 and 2 (IRS-1 and IRS-2) in the liver. This pathway includes a cascade of consecutive events. First, insulin-mediated stimulation of tyrosine phosphorylation of IRS is diminished. Subsequent to a decrease in IRS-associated phosphatidylinositol 3-kinase (PI3K) activity, the phosphorylation of AKT is depressed (Honma et al., 2018; Pagliassotti et al., 2002; Softic et al., 2020).

Experimentally, it has been shown that rats chronically fed a sucrose-rich diet (SRD) show metabolic and physiological characteristics that mimic several aspects of human MS. The animals exhibit glucose intolerance, IR, hypertension, dyslipidemia, visceral adiposity, and ectopic lipid accumulation in key tissues (liver, pancreas, skeletal muscle, cardiac muscle, and kidney) (Chicco et al., 2003; D'Alessandro et al., 2006; D'Alessandro et al., 2008; Rossi et al., 2010; Selenscig et al., 2010; Ferreira et al., 2010; Hein et al., 2012; Oliva et al., 2013; Ferreira et al., 2013; Creus et al., 2016; Ferreira et al., 2020). This is accompanied by oxidative stress, fibrosis, and a proinflammatory and prothrombotic state (D'Alessandro et al., 2015; Creus et al., 2017; Ferreira et al., 2018; Creus et al., 2020; Oliva et al., 2021a; Creus et al., 2022; Vega Joubert et al., 2022a; Vega Joubert et al., 2022b; Aiassa et al., 2022; Vega Joubert et al., 2025; Illesca et al., 2024; Aiassa et al., 2025).

Functional foods contain biologically active ingredients that are associated with physiological health benefits and contribute to the prevention and treatment of chronic diseases, such as T2DM (Alkhatib et al., 2017). Among these functional foods, chia (Salvia hispanica L.), an herbaceous annual plant, has attracted worldwide interest because of its nutraceutical advantages. These seeds are composed of different functional components, including omega-3 fatty acids, fiber, polyphenols, antioxidants, vitamins, minerals, and peptides (Khalid et al., 2022). The fatty acid profile is of particular interest. It is characterized by a high content of polyunsaturated fatty acids, mainly α-linolenic acid (C18:3 n-3, ALA), which constitutes approximately 60 % of all fatty acids (Kulczyński et al., 2019).

It has been previously shown that the administration of chia seed to rats fed a long-term SRD improved liver damage, steatosis, fibrosis, lipotoxicity, lipid peroxidation, oxidative stress, endothelial dysfunction, and inflammation in the liver (Oliva et al., 2021a; Vega Joubert et al., 2022a, 2022b). Therefore, to expand these findings, the aim of the present work was to evaluate the effects of chia seed, rich in α-linolenic acid (C18:3 n-3, ALA), on glucose tolerance, enzyme activities and transcription factors involved in gluconeogenesis, and key molecules in insulin signaling in SRD fed rats. In addition, the fatty acid composition of liver tissue phospholipids was analyzed after chia seed administration.