Molecular Mechanisms Against Successful Weight Loss and Promising Treatment Options in Obesity

Introduction: Obesity has become a major health issue, with multifactorial etiologies, involving lifestyle, genetic, and neuroendocrine mechanisms. Despite public health campaigns and lifestyle interventions, long-term weight loss is often difficult to achieve or sustain.Objectives: This literature review aims to summarize current knowledge on the main molecular mechanisms that hinder weight loss and to summarize the newest therapeutic strategies targeting obesity.Methods: The literature review was conducted using PubMed, Scopus, and Web of Science databases.Results: Obesity is a complex, chronic, recurrent metabolic condition that requires personalized, multidisciplinary treatment approaches. In this review, we summarize the major molecular mechanisms underlying weight gain and weight maintenance in obesity. In this literature review we address the thrifty gene hypothesis, the hypothalamic set point regulation, the metabolic memory and epigenetics in the maintenance of obesity and the metabolic adaptation to weight loss. The dysfunction of adipose tissue contributes to chronic low-grade inflammation and insulin resistance, leading to more severe disorders. The ratio of white, beige, and brown adipocytes also play an important role in regulating energy balance. Epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNAs, regulate long-term gene expression changes in response to lifestyle that can be passed on to further generations.Conclusions: Current interventions, including calorie restriction, physical activity, and pharmacological treatment together may show great promise in combating obesity but long-term efficacy and safety remain to be established.