Obesity and Its Comorbidities: Current Treatment Options, Emerging Biological Mechanisms, Future Perspectives and Challenges

Abstract

Obesity is a chronic, multifactorial disease and a major global public health challenge. Defined by excessive fat accumulation, obesity significantly increases the risk of numerous diseases, including type 2 diabetes mellitus (T2DM), cardiovascular disease, heart failure, and metabolic dysfunction-associated steatotic liver disease, contributing to rising morbidity and mortality rates worldwide. Although several pharmacological treatments have demonstrated notable efficacy in weight management, concerns regarding drug safety remain a significant challenge. Metabolic bariatric surgery (MBS) has emerged as the most effective intervention for achieving long-term and sustained weight loss; however, it is typically reserved for advanced stages of the disease. Moreover, the role of MBS in managing obesity-related comorbidities remains a topic of ongoing debate. In this review, we provide a comprehensive analysis of the epidemiology of obesity and its associated comorbidities, along with the latest insights into the mechanisms underlying obesity-induced chronic complications. Growing evidence highlights the crucial role of imbalances between white and brown adipose tissues, alterations in gut microbiota, genetic and epigenetic modifications, and immune system dysregulation in driving obesity and its related conditions. These emerging insights have unveiled numerous potential therapeutic targets with promising weight-reducing effects. Furthermore, advancements in our understanding of signal transduction pathways may pave the way for future multimodal therapeutic strategies in obesity management, ushering in a new era of precision medicine.

Keywords: clinical challenges; comorbidity; mechanism; obesity; treatment.

Figure 1

Mechanism of obesity and its comorbidities. Obesity is intricately associated with metabolic disorders, including NAFLD, T2DM, CVD, and CRC, through multifactorial pathophysiological mechanisms. (a) Imbalance of white and brown adipose tissues. WAT stores fat and promotes insulin resistance, contributing to metabolic disorders. In contrast, BAT enhances energy expenditure and thermogenesis, helping regulate metabolism and counteract obesity. (b) Gut microbiota dysbiosis. Obesity-related gut dysbiosis involves reduced probiotics and increased pathogenic bacteria, leading to inflammation, metabolic dysfunction, and impaired gut barrier integrity, which contribute to insulin resistance and related comorbidities. (c) Genetic and epigenetic alteration. Adipokine-related gene variants and fat distribution-associated polymorphisms contribute to inflammation and insulin resistance. Epigenetic modifications, such as RNA m6A methylation, regulate obesity and its complications, with FTO-dependent m6A modifications promoting adipogenesis, while METTL3 and YTHDF1 drive CRC via oncogenic pathways. (d) Immunity changes. Macrophage polarization and T cell alterations drive chronic inflammation, with NF-κB activation increasing TNF-α and IL-6 secretion. These interconnected mechanisms contribute to obesity-related comorbidities.

Figure 2

Treatment path for obese patients. In the absence of severe metabolic comorbidities, initial obesity management focuses on lifestyle interventions, including dietary modifications, physical activity, psychological support, and sleep optimization. Pharmacological therapies may be utilized as adjuncts to enhance weight loss when necessary. In patients with metabolic disorders, early consideration of metabolic surgery is warranted. If non-invasive approaches achieve sufficient weight loss, long-term adherence to lifestyle modifications is crucial. However, if conservative treatments fail, bariatric procedures, such as sleeve gastrectomy, may be performed, with Roux-en-Y gastric bypass as a subsequent option if needed. Post-surgical care requires lifelong monitoring and supplementation of vitamins and trace elements, with potential risks including dumping syndrome, internal hernia, and anastomotic leakage.