Aim: Prenatal nicotine exposure (PNE) alters the ă hypothalamic-pituitary-adrenocortical (HPA) axis-associated ă neuroendocrine metabolic programming in intrauterine growth retardation ă offspring rats. In this study we aimed to clarify the susceptibility to ă metabolic diseases of PNE offspring rats fed a high-fat diet. ă Methods: Maternal Wistar rats were injected with nicotine (1.0 mg/kg, ă sc) twice per day from gestational day 11 until full-term delivery, and ă all pups were fed a high-fat diet after weaning and exposed to ă unpredictable chronic stress (UCS) during postnatal weeks 18-20. Blood ă samples were collected before and after chronic stress, and serum ACTH, ă corticosterone, glucose, insulin, total cholesterol, triglyceride and ă free fatty acids levels were measured. The hypothalamus, pituitary gland ă and liver were dissected for histological studies. ă Results: UCS significantly increased the serum ACTH, corticosterone and ă insulin levels as well as the insulin resistant index without changing ă the serum glucose, total cholesterol, triglyceride and free fatty acids ă levels in adult offspring rats without PNE. The body weight of PNE ă offspring rats presented a typical ``catch-up'' growth pattern. PNE ă not only aggravated the UCS-induced changes in the HPA axis programmed ă alteration (caused further increases in the serum ACTH and ă corticosterone levels), but also significantly changed the glucose and ă lipid metabolism after UCS (caused further increases in the serum ă glucose level and insulin resistant index, and decrease in the serum ă free fatty acids). The effects of PNE on the above indexes after UCS ă showed gender differences. Pathological studies revealed that PNE led to ă plenty of lipid droplets in multiple organs. ă Conclusion: PNE enhances not only the HPA axis, but also the ă susceptibility to metabolic diseases in adult offspring rats fed a ă high-fat diet after UCS in a gender-specific manner and enhances the ă susceptibility to metabolic diseases in adult offspring rats fed a ă high-fat diet.