Gene expression of mineralocorticoid and glucocorticoid receptors in the limbic system is related to type-2 like diabetes in leptin-resistant rats

Diabetes is often accompanied by a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis which is regulated centrally via glucocorticoid (GR) and mineralocorticoid receptors (MR). Here, we compared the expression of both receptor subtypes in the brain of Zucker fatty and Zucker diabetic fatty (ZDF) rats together with their respective control rats. Both strains are primarily leptin resistant due to a mutated leptin receptor; ZDF rats, however, develop type-2 like diabetes. Using quantitative real-time PCR (qPCR) we found increased hypothalamic corticotrophin releasing hormone (CRH) levels in rats with the genetic ZDF background independently from leptin resistance. This was accompanied by elevated plasma corticosterone levels and by a higher reactivity of the HPA axis in response to CRH. Rats with the genetic ZDF background showed increased mRNA levels of GR in the amygdala and hypothalamus and increased mRNA levels of MR in the hippocampus and hypothalamus compared to rats with the Zucker fatty background. In leptin resistant ZDF rats but not in Zucker fatty rats, the mRNA levels of MR were selectively increased in the amygdala compared to nondiabetic control rats. No differences in the GR mRNA levels were found between leptin resistant Zucker fatty rats and lean control rats. Thus, an increased drive of the HPA axis in rats with ZDF background is associated with a differential expression of GR and MR in the limbic system. This dysregulation of the HPA axis may eventually lead, in combination with leptin resistance, to the development of diabetes in ZDF rats.