Pathophysiology and Mechanisms
- Adipose Tissue Biology and Dysfunction
- Neuroendocrine Regulation of Appetite and Energy Balance
- Inflammation and Immune Mechanisms in Obesity
- Role of Gut Microbiome
- Emerging Molecular Mechanisms in Obesity
- Translational Insights: From Mechanisms to Therapeutics
Obesity is a multifactorial chronic disease characterized by excessive adiposity that impairs health. The pathophysiology of obesity revolves around an energy imbalance, where caloric intake exceeds expenditure, leading to the accumulation of excess adipose tissue. Central to its development is the dysregulation of energy homeostasis, mediated by a complex interplay of genetic, environmental, and hormonal factors. The hypothalamus plays a critical role in regulating appetite and energy expenditure via neuropeptides such as neuropeptide Y (NPY), pro-opiomelanocortin (POMC), and agouti-related peptide (AgRP). Dysfunctions in these pathways, often influenced by genetic predispositions, alter satiety signals and promote increased food consumption. Adipose tissue itself acts as an endocrine organ, secreting adipokines like leptin and adiponectin. In obesity, leptin resistance disrupts normal signaling, leading to impaired appetite regulation and reduced energy expenditure despite elevated leptin levels. Insulin resistance, a hallmark of obesity, further exacerbates metabolic dysfunctions by impairing glucose uptake and fostering lipogenesis.
Chronic low-grade inflammation is another pivotal mechanism in obesity. Adipose tissue expansion results in hypoxia, cellular stress, and infiltration by pro-inflammatory immune cells, such as macrophages, which secrete cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These inflammatory mediators promote insulin resistance and contribute to the development of obesity-related comorbidities, including type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Mitochondrial dysfunction and oxidative stress in adipocytes further impair energy metabolism and perpetuate inflammatory responses. Additionally, alterations in the gut microbiota, or dysbiosis, have been implicated in obesity by influencing nutrient absorption, energy harvest, and systemic inflammation. Environmental factors, such as high-calorie diets rich in fats and sugars and sedentary lifestyles, interact with these biological mechanisms to perpetuate weight gain. Understanding the pathophysiology of obesity highlights the necessity of multifaceted approaches, encompassing lifestyle modifications, pharmacological interventions, and potentially bariatric surgery, to address its complex etiology and associated health burdens.
