Fig. 6. Working model for dysfunctional HPA axis activity in DIO rats.

Unlike DR rats that display appropriate NE-HPA responses to an exogenous leptin, DIO rats already show an uncoupling of the NE-HPA axis circuitry. Once exposed to HF diet, DIO rats exhibit worsened leptin signaling in the brainstem in a time-dependent manner that leads to increased noradrenergic input to CRH neurons in the PVN, however uncoupling to HPA axis ensues. We speculate that the early leptin resistance in NE neurons and exacerbated NE-HPA axis uncoupling likely lead to the development of obesity in the selectively bred DIO rats. Whether these neuroendocrine defects are attributed to high circulating FFAs or leptin resistance in DIO rats needs further investigation