Endocrine Abstracts

Neuronal glucose and insulin signals are integrated by hypothalamic neurons to regulate energy balance. These signalling mechanisms are not clearly defined in the hypothalamus, and may be altered in obesity and diabetes. This study aimed to analyse quantitatively hypothalamic expression of candidate genes in signal transduction pathways and investigate dysregulation using Zucker and Zucker Diabetic Fatty (ZDF) models.

Taqman RT-PCR was used to compare expression of candidate genes involved in glucose sensing in male, lean and obese, Zucker and ZDF rats at various ages. In order to validate the Taqman technique, hypothalamic neuropeptides were analysed. In 14-week-old Zucker rats, POMC expression was decreased (p<0.005) and AGRP and NPY expression increased in obese animals compared to lean controls (p<0.005, p<0.05 respectively).

Expression of the glucose sensing K_ATP channel component, Kir 6.2 was decreased in obese ZDF rats compared to lean ZDF rats at 6, 10 and 14 weeks of age (p<0.05, p<0.005). Over the development of diabetes (6-14 weeks), Kir 6.2 was also consistently lower in diabetic, obese ZDF compared to non-diabetic, obese Zucker rats (6 weeks p<0.005, 8 weeks p<0.05, 10 weeks p<0.005, 14 weeks p<0.0005). This pattern was mirrored in their lean counterparts, except at 14 weeks when Kir 6.2 mRNA increased in lean ZDF rats to a level similar to that in the lean Zucker rats.

These results indicate that Kir 6.2 expression in the hypothalamus is decreased in animal models of obesity and diabetes and suggests Kir 6.2 may be involved in the pathogenesis of these metabolic disorders.