<p>Obesity, a major modern health issue, currently has two approved therapeutic approaches: calorie-restricted diets and increased physical activity, both aimed at prompting the body to utilize fat stores. However, these strategies have not effectively addressed the global obesity epidemic, which continues to escalate. In addition to dieting and exercise, new pharmacological and surgical approaches to obesity treatment also face a significant issue: weight regain following initial weight reduction. The body seems to possess mechanisms that actively resist the loss of fat stores. Several mechanisms have been proposed to explain the body’s resistance to long-term loss of excess adipose tissue; however, the main mechanism is often overlooked in clinical practice. In this review, we addressed the influence of adipose tissue on brain functions. Obesity is typically accompanied by mild to moderate systemic chronic inflammation. Various factors may contribute to obesity-induced inflammation, including hypoxia resulting from hypertrophic adipocytes, cell death, and adipocyte senescence. It is crucial to know that obesity-associated inflammation can easily develop in the central nervous system, disrupting normal brain functions, particularly those related to metabolism, appetite, and weight regulation. Neuroinflammation linked to obesity may be the most compelling mechanism to explain why the body resists weight loss and experiences weight regain, as well as why it is hard to follow a lifestyle change to lose weight. Obesity leads to a complex interplay of inflammation, hormonal imbalances, alterations in neurotransmitter function, and changes in brain structure and functions. These factors collectively contribute to impaired metabolic control, increased appetite, and difficulty managing weight.</p> Graphical Abstract <p></p>