DNA hypermethylation of Kiss1r promoter and reduction of hepatic Kiss1r in female rats with type 2 diabetes

Kisspeptin, produced from the brain and peripheral tissues, may constitute an important link inmetabolic regulation in response to external cues, such as diet. The kisspeptin system is welldescribed in the brain. However, its function and regulation in the peripheral tissues, especiallyin relation to metabolic disease and sex differences, remain to be elucidated. As Kiss1 and Kiss1r,encoding for kisspeptin and kisspeptin receptors, respectively, are altered by overnutrition/fasting and regulated by DNA methylation during puberty and cancer, epigenetic mechanismsin metabolic disorders are highly probable. In the present study, we experimentally inducedtype 2 diabetes mellitus (DM2) in female Wistar rats using high-fat diet/streptozocin. Weanalysed expression and DNA methylation of Kiss1 and Kiss1r in the peripheral tissues, usingquantitative-reverse-transcription PCR (qRT-PCR) and pyrosequencing. We discovered differentialexpression of Kiss1 and Kiss1r in peripheral organs in DM2 females, as compared with healthycontrols, and the profile differed from patterns reported earlier in males. DM2 in females waslinked to the increased Kiss1 mRNA in the liver and increased Kiss1r mRNA in the liver andadipose tissue. However, Kiss1r promoter was hypermethylated in the liver, suggesting genesilencing. Indeed, the increase in DNA methylation of Kiss1r promoter was accompanied bya reduction in Kiss1r protein, implying epigenetic or translational gene repression. Our resultsdeliver novel evidence for tissue-specific differences in Kiss1 and Kiss1r expression in peripheralorgans in DM2 females and suggest DNA methylation as a player in regulation of the hepatickisspeptin system in DM2.