The International Classification of Diseases (ICD) defines obesity as a chronic, recurrent, and multifactorial disease, as well as an important risk factor for other noncommunicable diseases (NCDs) such as diabetes, heart disease, and cancer, among others. The prevalence of obesity is increasing at an alarming rate, particularly in middle-income countries. Of the 41 million annual adult deaths attributable to NCDs, 5 million are directly related to a high body mass index (BMI) (≥25 kg/m²). Projections indicate that by 2035, more than 750 million children and adolescents will be living with overweight or obesity, underscoring the urgency of addressing this global public health crisis (Atlas 2024²). In Venezuela, 30.9% of adult women (older than 18 years) and 24.7% of adult men are living with obesity. The prevalence of obesity is higher than the regional average of 30.7% for women and 22.8% for men.1

The World Health Organization (WHO) defines overweight as a BMI between 25 and 30 kg/m², while obesity is defined as a BMI > 30 kg/m². Obesity is often accompanied by dyslipidemia, hypertension, and glucose intolerance, and is also a risk factor for several diseases such as type 2 diabetes mellitus (T2DM), fatty liver disease, atherosclerosis, and gallstones. The increasing prevalence of obesity, driven by lifestyle changes, represents a serious global public health crisis.2 Therefore, it is essential to implement urgent preventive and therapeutic measures.

Patients with overweight or obesity present a complex pathophysiological profile characterized by metabolic abnormalities, oxidative stress, mitochondrial dysfunction, and altered immune responses. Dysregulation of adipose tissue biology is a key factor in initiating inflammatory processes associated with obesity. The activation of pattern recognition receptors, such as Toll-like receptors 2 and 4 (TLR2 and TLR4), in response to molecules released by various cells, triggers an inflammatory cascade underlying insulin resistance (IR), a cornerstone in the pathogenesis of this disease.3

Obesity is associated with low-grade chronic inflammation, partly triggered by TLR2 and TLR4 activation. Free fatty acids and endotoxemia, characteristic of the obese state, activate TLR4 expressed in adipocytes, which in turn induces nuclear factor kappa B (NF-κB) activation and the subsequent release of proinflammatory cytokines such as IL-6, IL-1β, TNF-α, and monocyte chemoattractant protein-1 (MCP-1). These inflammatory molecules contribute to the pathophysiology of obesity.4

Experimental studies have shown that inactivation of the TLR4 gene protects against inflammation and IR associated with obesity.5 Two polymorphisms in exon 3 of this gene (rs4986790 and rs4986791) alter TLR4 receptor function, correlating with various diseases, including obesity. In Caucasian populations, these polymorphisms are often inherited together and can be studied jointly.6

Interleukin 6 (IL-6), a pleiotropic cytokine, plays a key role in the complex network of the inflammatory response. Its ability to modulate both pro- and anti-inflammatory processes makes it an essential regulator of homeostasis. In the context of obesity, IL-6 emerges as a key mediator of low-grade chronic inflammation, contributing to the development of IR and metabolic dysfunction. Increased circulating IL-6 levels, particularly in the presence of excess abdominal fat, have been associated with a higher risk of developing these metabolic complications.7 The production of IL-6 is induced during inflammatory processes or infections through the action of IL-1 or tumor necrosis factor (TNF-α), or through activation of Toll-like receptors following the recognition of pathogen- or damage-associated molecular patterns.6 The expression of IL-6 is regulated by several factors, including the presence of functional polymorphisms in the promoter region. One of the most extensively studied polymorphisms in the IL6 gene is −174 G/C (rs1800795), which has been associated with altered IL-6 transcription and increased risk of obesity.6

Given the involvement of Toll-like receptors (TLRs) and IL-6 in obesity and IR, this study evaluated the association between the TLR4 Arg299Gly (rs4986790), TLR4 Thr399Ile (rs4986791), and IL6 −174 G>C (rs1800795) genetic polymorphisms and the development of obesity in a Venezuelan population.