The metabolic and molecular mechanisms linking fructose consumption to lipogenesis and metabolic disorders

The global rise in type 2 diabetes mellitus (T2DM) has been closely associated with excessive fructose consumption, particularly from processed foods and sugar-sweetened beverages. High fructose intake disrupts metabolic homeostasis, leading to hyperglycemia and lipid dysregulation. Yet, long-term investigations of fructose's effects are lacking, especially regarding gene expression mechanisms. This review examines the metabolic and molecular gene expression mechanisms linking fructose consumption to metabolic disorders, focusing on pathways that drive lipogenesis and insulin resistance. Fructose's insulin-independent (FII) nature allows its rapid hepatocyte uptake, bypassing key metabolic checkpoints. This unique pathway facilitates accelerated production of triglycerides and uric acid, contributing to insulin resistance, dyslipidemia, Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD, formerly NAFLD), potentially progressing to chronic liver disease. Key transcription factors mediate fructose-induced lipogenesis, notably sterol regulatory element-binding protein 1c (SREBP1c) and carbohydrate response element-binding protein (ChREBP). Elevated fructose levels stimulate the expression of lipogenic enzymes in hepatocytes, such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC). Fructose also enhances phosphofructokinase-2 (PFK-2) activity and suppresses pyruvate dehydrogenase kinase, promoting glycolytic flux and de novo lipogenesis. Based on these metabolic and gene expression profiles, this review highlights how fructose metabolism accelerates lipid accumulation, promotes insulin resistance, and triggers key lipogenic regulators, strengthening the biological and clinical plausibility of fructose's role in T2DM. Although fructose occurs naturally and is often perceived as harmless, excessive fructose intake poses significant metabolic risks, particularly when consumed in large amounts. This highlights the critical role of healthy dietary patterns and portion control in reducing these adverse effects. However, the long-term causal relationship between high fructose intake and the development of type 2 diabetes mellitus (T2DM) remains insufficiently understood. Therefore, there is a pressing need for well-designed prospective studies—especially in developing countries—to elucidate the long-term metabolic impact of fructose consumption. These findings reinforce the importance of dietary moderation and evidence-based policy interventions to curb the growing burden of fructose-related metabolic disorders.