Obesity is a complex multifactorial disease that accumulated excess body fat leads to negative effects on health. Obesity continues to accelerate resulting in an unprecedented epidemic that shows no significant signs of slowing down any time soon. Raised body mass index (BMI) is a risk factor for noncommunicable diseases such as diabetes, cardiovascular diseases, and musculoskeletal disorders, resulting in dramatic decrease of life quality and expectancy. The main cause of obesity is long-term energy imbalance between consumed calories and expended calories. Here, we explore the biological mechanisms of obesity with the aim of providing actionable treatment strategies to achieve a healthy body weight from nature to nurture. This review summarizes the global trends in obesity with a special focus on the pathogenesis of obesity from genetic factors to epigenetic factors, from social environmental factors to microenvironment factors. Against this background, we discuss several possible intervention strategies to minimize BMI.Obesity increases the likelihood of various diseases and conditions which are linked to increased mortality. These include Type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), metabolic syndrome (MetS), chronic kidney disease (CKD), hyperlipidemia, hypertension, nonalcoholic fatty liver disease (NAFLD), certain types of cancer, obstructive sleep apnea, osteoarthritis, and depressionTreating these conditions can place an additional load on healthcare systems: for example, it is estimated that obese have a 30% higher medical cost than those with a normal BMIAs related total health-care costs double every decade, treating the consequences of obesity poses an expensive challenge for patients More and more etiologies or defects that lead to obesity can be identified under the background of struggle between nurture and nature, genetic and epigenetic, environmental and microenvironment. We are increasingly understanding how food cravings are upregulated in obesity individuals’ brains, how gut hormones, adipose tissue, or gut microbiota regulate appetite and satiety in the hypothalamus, as well as the roles of gut dysbiosis played in obesity development and how dysfunction of glucose and lipids metabolism causes secondary health problems.