In obesity, endocrine and metabolic perturbations, including those induced by chronic activation of the hypothalamus–pituitary–adrenal axis, are associated with the accumulation of adipose tissue and inflammation. Such changes are attributable to a combination of genetic and epigenetic factors that are influenced by the environment and exacerbated by chronic activation of the hypothalamus–pituitary–adrenal axis. Stress exposure at different life stages can alter adipose tissue metabolism directly through epigenetic modification or indirectly through the manipulation of hypothalamic appetite regulation, and thereby contribute to endocrine changes that further disrupt whole-body energy balance. This review synthesizes current knowledge, with an emphasis on human clinical trials, to describe metabolic changes in adipose tissue and associated endocrine, genetic and epigenetic changes in the obese state. In particular, we discuss epigenetic changes induced by stress exposure and their contribution to appetite and adipocyte dysfunction, which collectively promote the pathogenesis of obesity. Such knowledge is critical for providing future directions of metabolism research and targets for treating metabolic disorders.Published version