Expression of orexigenic/anorexigenic neuropeptides in obese and diabetic rats with primary leptin resistance

The hypothalamus plays a critical role in the regulation of energy homeostasis. Food intake and energy expenditure is controlled by several hypothalamic peptides such as neuropeptide Y (NPY), prepro-orexin (PPO), melanin-concentrating hormone (MCH), agouti gene related peptide (AgRP), pro-opiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART). Leptin resistance caused by a mutated leptin receptor results in obesity without apparent diabetes in Zucker fatty rats. In contrast, Zucker diabetic fatty (ZDF) rats, a substrain of Zucker fatty rats, develop type-2 like diabetes. To evaluate a possible role of the orexigenic/anorexigenic hypothalamic peptides in the development of diabetes in ZDF rats we analyzed their gene expression by quantitative real-time PCR on a GeneAmp 5700 sequence detection system using SYBR green I as fluorescent dye. We compared rats with the genetic background of Zucker fatty and of ZDF rats either with or without mutated leptin receptors. In obese Zucker fatty rats and diabetic ZDF rats, hypothalamic POMC and CART mRNA levels were reduced compared to the respective control rats with intact leptin receptors. In addition, CART mRNA levels were significantly higher in rats with the genetic background of ZDF rats compared to rats with the genetic background of Zucker fatty rats. POMC mRNA levels were not different between the two genetic backgrounds. In ZDF but not in Zucker fatty rats, NPY mRNA levels were increased compared to controls. No differences between PPO, AgRP, and MCH were found between obese or diabetic rats and their control or between rats with the Zucker fatty or ZDF background. Elevated plasma corticosterone levels indicated an activated hypothalamo-pituitary-adrenal axis in rats with ZDF background. Our results reveal specific differences in the expression of hypothalamic peptides between the genetic background of Zucker fatty and ZDF rats. In combination with leptin resistance, the high expression of CART that is associated with high plasma corticosterone levels may be involved in the development of diabetes in ZDF rats.