DYSREGULATION OF ARCUATE NUCLEUS PREPRONEUROPEPTIDE-Y MESSENGER-RNA IN DIET-INDUCED OBESE RATS

Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) produce metabolic and physiological effects that promote the developm ent and maintenance of obesity. In turn, NPY metabolism in these neuro ns is inhibited by dopamine release. In this study, ARC prepro-NPY mRN A and ARC/median eminence (ME) dopamine turnover were assessed in chow -fed male Sprague-Dawley rats prone to develop diet-induced obesity (D IG) or to be diet resistant (DR) when fed a high-energy (HE) diet. By in situ hybridization, DIG-prone rats had 39% more ARC NPY mRNA expres sion than DR-prone rats under chow-fed conditions. DIG-prone rat ARC/M E dopamine levels were 14% higher, but dopamine half-life was 176% lon ger and turnover was 59% less than DR-prone rats. Neither a 48-h fast nor 50% energy intake restriction for 5 days affected the already incr eased ARC NPY mRNA levels in DIG-prone rats. Both manipulations increa sed NPY expression to the level of DIG-prone rats in DR-prone rats by 23 and 35%, respectively. Finally, when fed HE diet for 2 wk, neither DIO- nor DR-prone rats altered their ARC NPY expression despite the de velopment of obesity and hyperinsulinemia in DIO rats. Thus DIO-prone rats overexpress and fail to regulate ARC NPY mRNA to energy restricti on or hyperinsulinemia. This dysregulation is possibly secondary to re duced inhibition because of defective ARC/ME dopamine turnover. Both m ay be important predisposing factors in the development of DIO.