The social problems and medical burdens caused by obesity have become more serious in recent years. Obesity is mainly caused by the imbalance of energy intake and consumption in the body. The central nervous system and related neurons regulate the balance of energy metabolism. The hypothalamic arcuate nucleus (ARC) contains anorexigenic proopiomelanocortin (POMC) neurons and orexigenic neuropeptid Y(NPY)/agouti-related protein (AgRP) neurons that regulate the feeding behavior of body. High-fat diet induces phosphorylation of Rb protein in POMC neurons, and inactivation of Rb phosphorylation leads to re-entry of POMC neurons from the resting-state into the cell cycle, which rapidly shifts to apoptosis. High-fat diet also causes the inhibition of neuronal regeneration, induces inflammation and neuronal damage, loss of neuronal homeostasis, leptin resistance, and ultimately leads to obesity. This review discusses the relationship between loss of neuronal homeostasis and dietary obesity, as well as the underlying mechanisms, which might?provide the evidence for prevention and treatment of these diseases.