In spite of significant attention being devoted to the topic, overweight and obesity prevalence continues to increase worldwide. A systematic analysis performed in 2013 referred to the global burden of these conditions and showed that more than 50% of the world's 671 million obese people live in 10 countries. This special issue addresses a number of basic and clinical aspects of obesity, including the innate disease and hypothalamic genes controlling energy expenditure. It also covers inflammaging, the role of the melanocortin system in metabolic disease, hypothalamic lipids as key regulators of whole-body energy balance, hypothalamic insulin resistance, white adipose tissue and circadian rhythm dysfunction, and the high cardio-metabolic risk associated with phenotypes of Polycystic Ovary Syndrome. There is an attempt to provide an alternative pathogenic and therapeutic approach that will hopefully open new and promising avenues for disease prevention, appropriate control, and treatment. sakriti opis