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

Objectives: 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. 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, with a preference for peer-reviewed original articles, systematic reviews, and meta-analyses. Eligible studies were required to be published in the English language and within the last ten years (2015–2025), with the exception of historically significant publications. A total of 112 articles were included in our review. 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 metabolic memory and epigenetics that act through DNA and histone modifications and micro interfering RNAs, resulting in an energy imbalance that can be passed on to further generations. The dysfunction of adipose tissue contributes to chronic low-grade inflammation and insulin resistance, leading to more severe obesity. The ratio of white, beige, and brown adipocytes also plays an important role in regulating energy balance. Novel medical interventions offer promising results in attenuating these mechanisms against successful weight loss. 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.